pre-empt annual report 2013-2014 · introduction & overview pre-empt annual report 2013 - 2014...
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Picture 1: Accredited Social Health Activists (ASHAs) at Amingad Primary Health Centre, Karnataka, India showing off their CLIP POM devices. One of the ASHAs told us that having the POM was “like bringing the hospital to my home”.
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TABLE OF CONTENTS
COMMONLY USED ACRONYMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .VI
INTRODUCTION & OVERVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
LETTER FROM THE PRE-EMPT PRINCIPAL INVESTIGATOR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVE 1: PREVENTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
THE CAP (CALCIUM AND PRE-ECLAMPSIA) TRIAL: A WHO COLLABORATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
OBJECTIVE 2: MONITORING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
miniPIERS (PRE-ECLAMPSIA INTEGRATED ESTIMATE OF RISK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
COMMUNITY BLOOD PRESSURE MONITORING IN RURAL AFRICA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
MORTALITY AND MORBIDITY REVIEWS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
MATERNAL MORTALITY, AND MATERNAL MORBIDITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Maternal Mortality & Severe Acute Maternal Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Perinatal mortality and severe morbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
mHealth TO SUPPORT PREGNANCY HEALTH MONITORING IN CLIP AND BEYOND . . . . . . . . . . . . . . . . . . . . . . . . 18
PIERS ON THE MOVE (POM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
MAPPING OUTCOMES FOR MOTHERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
fullPIERS (PRE-ECLAMPSIA INTEGRATED ESTIMATE OF RISK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
EMMA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
CIPHER (COLLABORATIVE INTEGRATED PREGNANCY HIGH-DEPENDENCY ESTIMATE OF RISK) . . . . . . . 26
MEOWS (MODIFIED EARLY OBSTETRIC WARNING SYSTEM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
ECONOMIC EVALUATION OF THE CLIP TRIAL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
PLGF IN IUGR (PLACENTAL GROWTH FACTOR IN INTRAUTERINE GROWTH RESTRICTION) STUDY . . . . . 29
REMEMBERING ANDRÉE GRUSLIN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
OBJECTIVE 3A: TREATMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34
GYNUITY HEALTH PROJECTS ORAL ANTIHYPERTENSIVE TRIAL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
OBJECTIVE 3B: TREATMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36
CLIP (COMMUNITY LEVEL INTERVENTIONS FOR PRE-ECLAMPSIA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
CLIP FEASIBILITY STUDY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
CLIP Feasibility Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Mozambique CLIP Feasibility Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Nigeria CLIP Pilot TRIAL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Pakistan CLIP Pilot Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
India . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
STRIDER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
OBJECTIVE 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .50
THE GLOBAL PREGNANCY COLABORATORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
OBJECTIVE 5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54
KNOWLEDGE TRANSLATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
THE PREECLAMPSIA FOUNDATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
GLOBAL LIBRARY OF WOMEN’S MEDICINE HDP TEXTBOOK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
PRE-EMPT ADVOCACY, GLOBAL ACCESS AND SELECT PUBLICATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
PARTNERSHIPS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
APPENDICES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Appendix A: Steering Committee Members . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Appendix B: COLAB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
(Green highlighted text indicates funding by BMGF)
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AKU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aga Khan University
APACHE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acute Physiology And Chronic Health Evaluation
APE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Agente Polivalente Elementares
APTT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Advanced Partial Thromboplastin Time
AWW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anganwadi Workers
CAP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Calcium And Pregnancy
cHCPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Community Health Care Providers
CHIPS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Control of Hypertension in Pregnancy Study
CI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Confidence Interval
CIPHER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Collaborative Integrated Pregnancy High-dependency Estimate of Risk
CLIP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Community Level Interventions for Pre-eclampsia
CME . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Continuous Medical Education
CPD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Continuous Professional Development
cRCT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cluster Randomised Control Trial
C/S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Caesarean section
dBP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Diastolic blood pressure
DIC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disseminated Intravascular Coagulation
EDD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Estimated Date of Delivery
EMMA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Evaluating Maternal Markers of Adverse placental outcomes
EmONC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Emergency Obstetric and Neonatal Care
FGD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Focus Group Discussion
FIGO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . International Federation of Gynecology and Obstetrics
GAPPS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Global Alliance to Prevent Prematurity and Stillbirth
GIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Geographic Information Systems
GSK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Glaxo Smith Kline
HELLP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Haemolysis, Elevated Liver Enzymes, Low Platelets
HIE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypoxic Ishaemic Encephalopathy
ICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intensive Care Unit
IDI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . In-Depth Interview
IFPA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . International Federation of Placental Associations
i.m. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intramuscular
IPD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Individual Participant Data
ISSHP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . International Society for Study of Hypertension in Pregnancy
IUGR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intrauterine Growth Restriction
i.v. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intravenous
Jhpiego . . . . . . . . . . . . . . . . . . . . . . . . . . . . Johns Hopkins Programme for International Education in Gynecology and Obstetrics
KT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Knowledge Translation
LGA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Local Government Area
LHW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lady Health Worker
LMICs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Low and Middle Income Countries
LMP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Last Menstrual Period
LR+ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Positive Likelihood Ratio
M&M . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Morbidity and Mortality
MAPEDIR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Maternal and Perinatal Death Inquiry Response
MCHIP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Maternal and Child Health Integrated Programme (USAID)
MDR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Maternal Death Rate
MEOWS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Modified Early Obstetric Warning System
mHealth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mobile Health
MOM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mapping Outcomes for Mothers
MM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Maternal Mortality
MMR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Maternal Mortality Ratio
MMWG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . WHO Maternal Morbidity Working Group
MOH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ministry of Health
NGO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-Governmental Organisation
OOUTH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Olabisi Olabanjo University Teaching Hospital
PHC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Primary Health Centre
PIERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pre-eclampsia Integrated Estimate of RiSk
p.o. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . By Mouth
POM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PIERS On the Move
PPH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Postpartum Hemorrhage
RCT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Randomised Controlled Trial
ROC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Receiver Operating Characteristic
SA NDOH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . South African National Department of Health
sBP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Systolic Blood Pressure
SFH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Symphysis-Fundal Height
SOGC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Society of Obstetricians and Gynaecologisits of Canada
SOGON . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Society of Gynecology and Obstetrics of Nigeria
TBA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Traditional Birth Attendant
UBC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . University of British Columbia
UCSF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . University of Clalifornia San Francisco
UEM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Universidade Eduardo Mondlane
UNFPA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . United Nations Population Fund
WHO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . World Health Organization
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2014INTRODUCTION & OVERVIEW
LETTER FROM THE PRE-EMPT PRINCIPAL INVESTIGATOR
Welcome to the 2013–2014 PRE-EMPT Annual Report. This fourth annual report provides a summary of the project goals, activities, milestones, and plans within the PRE-EMPT research programme, with a specific focus on the fourth 12 months’ activities (since November 2013) and plans for the next 12 months.
It is with gratitude and a sense of wonder at what this team has achieved over the past year that I write this summary and introduction to the report. If we were busy and productive over the preceding three years, that level of activity has been eclipsed. In terms of milestones met, leveraged funding received, academic outputs, and advocacy, this has been our best year to date and the outputs are growing exponentially.
Our most important announcement of the year is that Jim Roberts and the Magee Women’s Research Institute received additional funds from the Gates Foundation to support the Global Pregnancy CoLaboratory for an additional three years, co-terminating with the remainder of the current funding envelope for the PRE-EMPT initiative. This is a major renewal of the Foundation’s investment in the CoLab, and should see it through to self-sustainability from peer-reviewed, agency, donor, and industry sources. Personally, as an investigator who retains a wet laboratory discovery science presence, I am delighted that we will be able to strengthen the CoLab’s interest in the origins and consequences of placenta-derived pregnancy complications that are specific to less developed countries and those that are common globally.
Other funding successes leveraged against the success and stature of PRE-EMPT this year were significant funds from: (i) Saving Lives at Birth (through Grand Challenges Canada) to further develop the PIERS on the Move platform, focusing on newborn screening; (ii) CIHR for temporal and external validation of the fullPIERS model; (iii) CIHR for the Canadian STRIDER trial, a placebo-controlled, randomised controlled trial of sildenafil in early onset placental fetal growth restriction (one of a consortium of five international STRIDER trials sharing the UBC infrastructure established by PRE-EMPT); and (iv) the Sabrina’s Foundation to support the publication, by GLOWM, of an evidence-based, globally-relevant, and free to less developed country colleagues textbook (and supporting digital and print materials) to inform the care of women whose pregnancies are complicated by the hypertensive disorders of pregnancy. In addition, we have further leveraged funds through discounted bulk purchases from cell phone and tablet as well as drug and device manufacturers.
The past year has seen a close to doubling of recruitment to the Calcium And Pregnancy (CAP) Trial due to the combined efforts of Justus and Mandisa, the site investigators and research midwives in all three countries, South Africa, Zimbabwe, and Argentina. The systematic review of low-dose calcium for the prevention of pre-eclampsia (and its complications) was
published in BJOG this year, and is having an impact on policy and programme implementation. Tina Purnat has moved to the WHO Europe Office, and I’d like to thank her for her vital input as the trial was established and gained momentum. I had the privilege of joining the CAP team for their annual meeting in March—it was an inspiration to work and spend time with such a dedicated team, even if the spectacular view of Table Mountain out the window was somewhat distracting.
For the monitoring objective, this past year has been one of converting a concept of the PIERS on the Move app into a reality that has now guided the antenatal care of women in Nigeria, Pakistan and India for over 14,000 visits, and resulting in over 250 urgent and non-urgent referrals to facility. The miniPIERS paper was published in PLoS Med and the PIERS on the Move app development paper in IEEE J Biomed Health Inform. Also, we have published two papers related to pre-eclampsia surveillance (proteinuria and uric acid) in JOGC. One further paper is in press (added value of pulse oximetry to miniPIERS) and another submitted (usability testing of the app). Parallel, CIHR-funded, modelling work is well-advanced for fullPIERS validation and the development and validation of the CIPHER model for pregnant and recently pregnant women admitted to ICU.
For objective three, Treatment, I am delighted to have the data from the Gynuity Health Projects Oral Antihypertensive Trial pilot study that shows that the trial should proceed with all three agents, namely labetalol, nifedipine and, too many peoples’ surprise, methyldopa. Process logjams have been overcome and the trial will begin recruiting over the next couple of months. CLIP Feasibility Study work is completed in Mozambique, with important results that have informed the specific design of the CLIP Mozambique Trial. This has enabled us to begin writing the Feasibility Study manuscripts, and I anticipate a flurry of academic output from this important activity over the next 12 months. The CLIP Pilot Trials in Pakistan and India are completed, with the Nigerian CLIP Pilot Trial recruiting until March 2015. As we meet in Seattle for our annual meeting, the Definitive CLIP trials in Mozambique, Pakistan and India will either have been or just about to be launched. The combined effort of the UBC and country teams has been prodigious and I cannot thank each of you enough for the dedication and long hours that have contributed to getting us to this place. By this time next year, we will have submitted the Pilot Trials for peer-review, and, hopefully, these papers will be in press/published. In addition, we published systematic reviews of oral antihypertensive use in pregnancy
and puerperium (BJOG) and magnesium sulphate use in less developed countries (JOGC), and the CHIPS Trial paper is in press. Sadly, we mourn the death from breast cancer of a dear friend and colleague, Andrée Gruslin, who was such an important and ebullient member of the PIERS, CHIPS and STRIDER projects.
In addition to the great news about strengthened funding, the Global Pregnancy CoLaboratory has accelerated its momentum with two key, standard-setting papers in Hypertension and Placenta. An important statistics methodology manuscript has arisen from the angiogenic factor project and is submitted for peer review. The number of CoLab-co-ordinated projects has grown exponentially and will be the key to self-sustainability over time as an increasing number of these projects have external funding and can contribute to CoLab. A vision of greater outreach to, and partnership with, colleagues from less developed countries has become a core value within CoLab. The annual meetings in Oxford are intellectually stimulating and important as they create an exciting vision of what the future may hold for pre-eclampsia and placental disease research.
For knowledge translation, our partnership with the Preeclampsia Foundation remains strong as the input from the Foundation continues to inform our vision and priorities. The active partnership of the Preeclampsia Foundation’s Registry with CoLab is exciting and important. Engagement with the WHO remains strong through the Maternal Morbidity Working Group and the UN Commodities Commission, and I
am looking forward to beginning to plan for the next iteration of the WHO recommendations for pre-eclampsia and eclampsia. Within the PRE-EMPT group itself, our dominant knowledge translation activity this year coming year will be the production of the GLOWM pregnancy hypertension textbook in time for next year’s FIGO Congress. This will bring together the best global evidence, much of it collated by members of the PRE-EMPT team through their leadership of, and participation in, national guideline committees.
As always, I have many people to thank for our achievements and the consistent enjoyment brought to me by PRE-EMPT over the past year—too many to name personally other than very few. First, I must thank Sharla Drebit who has brought a calm effectiveness and diligence to her role of managing this complex entity. In addition, she has become a ‘go to’ person for colleagues locally and internationally as they think about and plan global maternal and child health projects. The objective PIs and all the individuals who give their precious time and intellectual space to this initiative are the reason for our continued progress and success. Laura’s and my children, and Sheila, my mother-in-law, are owed a great debt of gratitude and love for their understanding of my travel related to this project and their pride in what it is beginning to be achieved, while I acknowledge unreservedly that none of this would be achieved without Laura’s love, support, and intellectual contribution—it means everything to me. A personal highlight of the year was sharing with Laura the highest accolade of the International Society for the Study of Hypertension (ISSHP), the
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Picture 2: Peter von Dadelszen with the CLIP Nigeria team and surveillance officers during the CLIP Nigeria Pilot launch in early 2014. The orange vest is the instated uniform for the data collectors working in the CLIP Nigeria trial.
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2014Chesley Award, for distinguished research into hypertension in
pregnancy. In addition, Laura is now the president-elect of the ISSHP (president, 2016–18) and the International Society of Obstetric Medicine (ISOM, president, 2018–22).
Finally, I would like to take this opportunity to thank France Donnay, Senior Program Officer, Maternal Health, at the Gates Foundation, and friend, for her inspirational leadership in women’s health for decades, and, more specifically, for her guidance, advice, and support during the first four years of the PRE-EMPT initiative (and the preceding seven months of grant writing and revision). France, who has announced her impending retirement from the Foundation, has enabled an established pre-eclampsia and pregnancy hypertension research team, and its leadership, to transition from being enthusiastic newcomers to global health to whatever level of competence our peers feel that we have achieved to date. It would not have happened without her friendly and firm counsel, and my personal development in global health has been largely framed through France’s lens. However, what has been as important to me has been getting to know a highly cultured woman of broad interests and a dedicated grandmother with an absolutely disarming and charming sense of humour. About six months into the PRE-EMPT project we had one of our regular teleconferences with France, who happened to be in New York. She took the call sitting on a bench in Central Park. At the end of the allotted time for the call, she said, in her delightful French accent and conversational efficiency, “Okay, okay … it’s started raining in my office … time to finish now … bye, bye!” I am delighted that France has agreed to join the PRE-EMPT Technical Advisory Group for the remainder of the project.
Thank you all for your interest and support as we enter the fifth year of this great adventure working for the world’s girls and women (and their families) to whom this work is dedicated.
Peter von Dadelszen
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2014OBJECTIVE 1: PREVENTION
THE CAP (CALCIUM AND PRE-ECLAMPSIA) TRIAL: A WHO COLLABORATIONPrincipal Investigator:G Justus Hofmeyr
Funding:Bill & Melinda Gates Foundation World Health Organization
OVERVIEW
There is an epidemiological association between pre-eclampsia and low dietary calcium. Randomised trials of calcium supplementation in the second half of pregnancy have not shown sufficiently consistent effect to confirm the epidemiological observations as causal. We have hypothesized that early pregnancy (when placentation takes place) may be the time at which any effect of calcium deficiency on the development of pre-eclampsia might be mediated.
The CAP study is a unique pregnancy intervention trial in that recruitment takes place prior to pregnancy. Women with a history of pre-eclampsia in their most recent pregnancy and not using contraception, who agree to participate, receive calcium 500mg daily or placebo from enrolment until they become pregnant, and up to 20 weeks of pregnancy. After 20 weeks all women receive calcium supplementation 1.5g daily according to WHO recommendations.
The protocol has been registered with the Pan African Trials registry, and published in the Lancet.
YEAR FOUR PROGRESS
Recruitment
Since last year’s report our recruitment has almost doubled to 896 women at the end of August 2014 (vs 446 on 24 July 2013). This is a remarkable achievement, due to concerted efforts at all the sites and active support from the team at WHO RHR. The number of pregnancies stands at 296 at the end of October 2014, with 229 delivered. By the time of the next DMSC meeting in February 2015, we can expect to have 320 pregnancies with 260 delivered. If the overall pre-eclampsia rate remains at 30%, we will require 318 deliveries to answer the original question, that is to be able to detect a 40% reduction in pre-eclampsia with 80% power. Therefore, we are hopeful that the DMSC will be in a position to advise us on the appropriate final sample size for the trial, and we may be close to achieving that size.
Dietary calcium assessment
Gabriela Cormick from the National University of LaMatanza in Argentina has made several visits to Southern African sites for training in dietary calcium assessment as part of an Argentina-South Africa Co-operation agreement.
Urinary calcium excretion study (Sub-study 4)
Sarah Manyame, Co-PI at Harare University, and Jim Roberts have worked on the standard operating procedures for urine collection, and most sites now have access to ultra-low temperature freezers for storage. Urine samples are being collected and stored at baseline, 20 weeks and 32 weeks of pregnancy to measure urinary calcium/creatinine ratio, in order to determine the relationship between dietary calcium intake and urinary calcium excretion, the effect of calcium supplementation on urinary calcium excretion, and the relationship between low urinary calcium excretion and risk of pre-eclampsia. In addition, we plan to compare urine protein/creatinine ratios between the calcium and placebo group at 32 weeks’ gestation.
We are exploring sources of co-funding for the laboratory work, as well as the possibility of collecting blood for further exploratory work on possible mechanisms of action of calcium supplementation.
Global Pregnancy Co-Laboratory
The urine samples being collected and stored will be available to the PRE-EMPT Global Pregnancy Co-Laboratory project, led by Jim Roberts.
CAP Study Recruitment
Month and Year
Num
ber
of W
omen
SCR ADM PREG DEL EOS
SCR 1837
ADM 896
PREG 296
DEL 229
2000
1800
1600
1400
1200
1000
800
600
400
200
0
Jul 2
011
Aug
2011
Sep
2011
Oct 2
011
Nov
2011
Dec
2011
Jan
2012
Feb
2012
Mar
201
2
Apr 2
012
May
201
2
Jun
2012
Jul 2
012
Aug
2012
Sep
2012
Oct 2
012
Nov
2012
Dec
2012
Jan
2013
Feb
2013
Mar
201
3
Apr 2
013
May
201
3
Jun
2013
Jul 2
013
Aug
2013
Sep
2013
Oct 2
013
Nov
2013
Dec
2013
Jan
2014
Feb
2014
Mar
201
4
Apr 2
014
May
201
4
Jun
2014
Jul 2
014
Aug
2014
Sep
2014
Oct 2
014
Figure 1: CAP Study Recruitment: SCR=Screened; ADM=Admitted; PREG=Pregnant; DEL=Delivered; EOS=End of Study.
Trial activities
We took advantage of the fact that Justus Hofmeyr, Ana Pilar Betrán, José Belizán, Eduardo Bergel and Fernando Althabe were attending a WHO meeting in Buenos Aires on the Odon device on 12–13 December 2013, to meet with and present the CAP study to members of the Institute of Clinical Effectiveness and Health Policy (IECS) and the participating Hospitals. During the meeting Justus Hofmeyr presented an update of the study and suggestions on how to improve recruitment and follow up. The local team presented a summary of the study implementation in Argentina. Discussions were held around how to improve follow up of women and definition of pregnancy. Attending the meeting in addition to those mentioned above were Gabriela Cormick, Maria Luisa Cafferata, Ricardo Lopez, Daniela Colaci, from IECS and Javer Schvartzman and Hugo Krupitzki from Centro de Educación Médica e Investigaciones Clínicas (CEMIC), Buenos Aires.
A visit to the monument to victims of state terrorism in the 1970’s highlighted the central role of Argentina in the historical background to the CAP study. It was after the disappearance of his brother, Fernando Alberto Belizán and sister-in-law Analia Alicia Arriola that José Belizán moved to Guatemala where the
strikingly low rates of pre-eclampsia compared with Argentinian women led to his hypothesis that dietary calcium may be protective against pre-eclampsia.
Data management
In June, our data manager, Tina Dannemann Purnat, took up a job with the WHO Office in Europe and she is based now in Copenhagen, Denmark, and was no longer able to work on the CAP trial. We all are grateful to Tina for her professionalism and commitment to the trial during the last three years.
Our trial collaborators in IECS in Buenos Aires, Argentina, took over the function of data management in July. IECS had already been involved in data management in our trial as they had coordinated and assumed part of this role at the sites in Argentina (three hospitals in Buenos Aires and one in Tucuman). We have now expanded this function for all the sites in the trial. We are working more on a day-to-day basis with Alvaro Ciganda and Gabriela Cormick. Gabriela has already been part of the trial as the coordinator of the site in Argentina. Alvaro is a systems analyst based in Uruguay and has worked in data management and other related activities for twelve years.
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2014He works with the Montevideo Clinical and Epidemiological
Research Unit (UNICEM) in Uruguay and with IECS in several multi-centre clinical trials in the Americas. Alvaro is 45 years old, married and has two children, a boy and a girl.
We are particularly grateful to the WHO team for providing the technical and financial support for data management, and for overseeing this transition.
WHO visits to sites
Most recently, two sites were visited by the WHO monitoring team: Johannesburg (11–14 March 2014) and Harare (10–14 April 2014). The team reported that it is always a big privilege to share a few days with the CAP local teams, join the trial visits and to meet the women who are shaping the trial and making our study a reality month after month.
Fourth Steering Committee Meeting, 8–9 March 2014
The CAP Study steering committee and representatives of the site researchers met at the Lagoon Beach Hotel, Cape Town on 9–10 March. Our thanks to Sumedha Sharma and Carol Phipson for perfect arrangements.
Peter von Dadelszen provided context for the CAP study by outlining the PRE-EMPT initiative and progress to date. We went through the year 3 trial report, prepared by Ana Pilar Betrán, Armando Seuc and Tina Purnat. Up to 1 February 2014, 1312 women had been screened; 586 randomised; 195 had become pregnant (33%); Of 127 completed pregnancies, 19 (15%) had miscarried, 2 terminations of pregnancy, 37/106 (35%) had developed pre-eclampsia and 11/106 (10%) had had stillbirths. Two participants have died, and these death were unrelated to participation in the trial. These data indicate that we are indeed recruiting a very high risk group of women. In adition to a history of pre-eclampsia, many women have had very severe pre-eclampsia, eclampsia, HELLP syndrome and perinatal loss in the previous pregnancy. All site study PI’s reported on progress at their sites, and we discussed issues relating to the protocol and optimizing recruitment. We considered the report of the DMSC referred to above. We discussed plans and responsibilities for sub-studies. Jim Roberts joined by telephone for discussion of the CoLaboratory work. Peter von Dadelszen identified the potential for collaboration with researchers currently working on Congo Red measurement, and Sarah Manyame and Jim Roberts are following up on this work. The meeting highlighted the commitment of our whole team to this important study. By 25 March the number of women randomised had already increased from 586 to 642.
Picture 3: Calcium and Pre-eclampsia Study Meeting participants (from left): Justus Hofmeyr, Stephen Munjanja, José Belizán, Ana Pilar Betrán, Armando Seuc, Gabriela Cormick, David Hall, Emelia Makaza, Sue Fawcus, Hannes van der Merwe, Pamela Njikelana, Velisa Mqikela, Xoliswa Williams, Peter von Dadelszen, Erika van Papendorp, Catherine Parker, Mandisa Singata-Madliki, Karlyn Frank, Patience Moloi. Jim Roberts joined by teleconference for the Colaboratory discussion. Unable to attend: Eduardo Bergel, Natalia Novikova, Tina Purnat and
Sharla Drebit.
Data Monitoring and Safety Committee Report
The DMSC for the Calcium and Pre-eclampsia (CAP) Study chaired by Prof Caroline Crowther met to review the CAP trial’s progress using available data on 24 February 2014.
“The conclusion of the Data Monitoring Committee was that there was no need to recommend changes to the current study protocol, no specific action was needed and that the CAP Study should continue as planned.”
Hopefully by the time of the 3rd DMSC interim analysis march 2015 there will be sufficient data to know whether the sample size can be reduced. We have been approved a no-cost extension to approximately the end of 2016.
Interaction with other projects:
1. Systematic review of low-dose calcium
There is considerable global interest in the concept of lower-dose calcium supplementation for pregnant women, and we have been asked to present results at several international meetings (see below). We are aware of a large randomised trial comparing supplementation with 600mg versus 1200mg taking place in China. Daniel Roth, University of Toronto, has been able to use the information from our systematic review of low-dose calcium supplementation for preventing pre-eclampsia as a basis for the calcium co-intervention in their planned prenatal vitamin
D supplementation trial in Bangladesh (funded by the Bill & Melinda Gates Foundation through the Healthy Growth program).
2. Eclampsia mortality in Northern Nigeria
We have been approached by a group in Northern Nigeria where the calcium and vitamin D status of the population is exceptionally poor, and the incidence and mortality from eclampsia are alarmingly high. They are interested in studying the problem, and we have discussed with them the option of a trial of intravenous calcium treatment for women presenting with eclampsia.
3. GSK Maternal and Neonatal Health, R&D Alternative Discovery & Development Unit
We have ongoing discussions with the research unit at GSK regarding the possibility of conducting mechanistic studies on the effects of calcium supplementation within the CAP study.
4. Chinese randomised trial of low vs high dose calcium supplementation
We have initiated discussions with investigators from West China Medical School/West China Second University Hospital, Sichuan University, Chengdu, China, regarding their ongoing randomised trial.
Anecdote: why trial participants have better outcomes than non-participants
It is well known that the extra attention paid to research subjects is generally associated with better health outcomes. This anecdote is a concrete example of how such benefits may accrue.
Participants in the CAP study have ready phone access to our research staff. At one of our sites, a participant contacted the research midwife to say that she was worried. She had started to swell up just as she had before losing her baby in her previous pregnancy. She had gone to the hospital antenatal clinic where she had been checked, reassured and told to return after 2 weeks. The CAP study midwife urged her to come and see her at once. She was reluctant to disobey the instruction to return only after 2 weeks, but was persuaded to return. Our midwife found that she had developed pre-eclampsia, and referred her back to the hospital where her baby delivered safely the same day. The outcome may not have been as good had she not had access to advice from the CAP study midwife.
Outputs of the CAP study
Input to South African National Department of Health
The CAP study PI has been approached by the South African National Department of Health for input on the recommendations of the National Essential Medicines List Committee regarding national guidelines for calcium supplementation during pregnancy. Based on our work outlined below we have recommended that if calcium supplementation is introduced at a primary care level the lower dose (500mg daily) should be considered on the basis of, acceptability/compliance, minimising risk of harm, current evidence of effectiveness and affordability.
Publications and presentations
The systematic review by the CAP study group aimed at reviewing the impact of lower dose calcium supplementation on pre-eclampsia risk was published in the BJOG on 13 March, 2014. The article is open-access and can be accessed at: http://onlinelibrary.wiley.com/doi/10.1111/1471–0528.12613/pdf. A very early impact of this publication has been a general agreement by Jhpiego in Nepal to do national rollout with 500mg of calcium supplementation. This is an important step towards improving maternal health and preventing pre-eclampsia.
Our review is the first to focus on the potential benefits of doses of calcium below the 1.5 to 2g recommended by WHO. Apart from acting as a basis for further research, it will inform policy on calcium supplementation programmes, given the logistical difficulties with implementing the high dose recommended by WHO.
An interesting finding highlighted in the review was that in the only trial of low-dose calcium supplementation in which supplementation was commenced before 12 weeks’ gestation, there was an unexpected trend to reduced miscarriage with calcium supplementation. The CAP study provides the opportunity to confirm or refute this observation (CAP sub-study 3: The effect of pre-pregnancy calcium supplementation on early pregnancy loss).
Low-dose calcium supplementation for preventing pre-eclampsia: a systematic review and commentary.
Background
Epidemiological data link low dietary calcium with pre-eclampsia. Current recommendations are for 1.5–2 g/day calcium supplementation for low-intake pregnant women, based on randomised controlled trials of ≥1 g/day calcium supplementation from 20 weeks of gestation. This is problematic logistically in low-resource settings; excessive calcium may be harmful; and 20 weeks may be too late to alter outcomes.
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Objectives
To review the impact of lower dose calcium supplementation on pre-eclampsia risk. Search strategy and selection criteria We searched PubMed and the Cochrane Pregnancy and Childbirth Group trials register. Data collection and analysis Two authors extracted data from eligible randomised and quasi-randomised trials of low-dose calcium (LDC, <1 g/day), with or without other supplements. Main results Pre-eclampsia was reduced consistently with LDC with or without co-supplements (nine trials, 2234 women, relative risk [RR] 0.38; 95% confidence interval [95% CI] 0.28–0.52), as well as for subgroups: LDC alone (four trials, 980 women, RR 0.36; 95% CI 0.23–0.57]); LDC plus linoleic acid (two trials, 134 women, RR 0.23; 95% CI 0.09–0.60); LDC plus vitamin D (two trials, 1060 women, RR 0.49; 0.31–0.78) and a trend for LDC plus antioxidants (one trial, 60 women, RR 0.24; 95% CI 0.06–1.01). Overall results were consistent with the single quality trial of LDC alone (171 women, RR 0.30; 95% CI 0.06–1.38). LDC plus antioxidants commencing at 8–12 weeks tended to reduce miscarriage (one trial, 60 women, RR 0.06; 95% CI 0.00–1.04).
Conclusions
These limited data are consistent with LDC reducing the risk of pre-eclampsia; confirming this in sufficiently powered randomised controlled trials would have implications for current guidelines and their global implementation.
Presentations by the Calcium and Pre-eclampsia (CAP) Study Group
• Hofmeyr GJ, for the Calcium and Pre-eclampsia (CAP) Study Group. Calcium supplementation for preventing pre-eclampsia/eclampsia. Africa Regional Meeting for Interventions for Impact in essential obstetric and newborn care. Addis Ababa, 21–25 February 2011.
• Hofmeyr GJ, Singata M, Fawcus S, Belizán JM, Oyebajo AB, Munjanja SP, Sawchuck D, von Dadelzsen P, Bergel E, Betran AP, Purnat T, Tahuringana E. Long term calcium supplementation in women at high risk of pre-eclampsia: a randomised, placebo-controlled trial. 31st Conference on Priorities in Perinatal Care in Southern Africa. Kruger Park, South Africa, 6–9 March 2012.
• Hofmeyr GJ, for the Calcium and Pre-eclampsia (CAP) Study Group. Use of calcium and vitamin D for prevention of pre-eclampsia/eclampsia. USAID MCHIP Asia Regional Meeting on Interventions for Impact in Essential Obstetric and Newborn Care, Dhaka, Bangladesh, 3–6 May 2012.
• Hofmeyr GJ, for the Calcium and Pre-eclampsia (CAP) Study Group. Low dose calcium supplementation for preventing pre-eclampsia: A systematic review and commentary. 32nd Conference on Priorities in Perinatal Care in Southern Africa, Mpekweni Beach Resort, 12–15 March 2013.
• Hofmeyr GJ. Calcium and Pre-eclampsia, Nutrition meeting, Birchwood Hotel, Johannesburg, 14 April 2013.
• Hofmeyr GJ. Evidence and global health: constraints and ethical dilemmas. African Cochrane Indbaba, Cape Town, 6–8 May 2013.
• Manyame S, Hofmeyr GJ. Pre-pregnancy calcium supplementation for the prevention of pre-eclampsia. African Cochrane indaba, Cape Town, 6–8 May 2013.
YEAR FIVE ANTICIPATED DELIVERABLES
During year 5 we expect to publish our sub-study on pre-pregnancy blood pressure. This will be the first randomised trial reporting the effects of calcium supplementation on blood pressures of non-pregnant women with previous pre-eclampsia.
In February 2015 the DMSC will meet to review trial data. We anticipate that there will be sufficient data to enable the DMSC to re-calculate the sample size required to answer the primary trial question. This should enable us to set a target for completion of recruitment.
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2014OBJECTIVE 2: MONITORING
miniPIERS (PRE-ECLAMPSIA INTEGRATED ESTIMATE OF RISK) Principal Investigator:Peter von Dadelszen
Trainee & Co-ordinator: Beth Payne
OVERVIEW
miniPIERS Overview
The hypertensive disorders of pregnancy (HDP) are the leading causes of maternal death and morbidity in low-resourced countries due to delays in case identification and a shortage of health workers trained to manage the disorder. The objective of the miniPIERS study was to develop an evidence-based tool that can aid community-based health workers in decision making around the care of women with hypertensive disorders of pregnancy; to provide distributed, personalized care for the most vulnerable.
YEAR FOUR PROGRESS
Over the past three years, we have achieved the objective of the miniPIERS study using a prospective cohort of data collected in five low-and middle-income countries to: (1) develop a clinical risk predication model using logistic regression (the “miniPIERS” model); (2) validate the miniPIERS model through bootstrapping and by applying the model to a second cohort of women with HDP; (3) extend and recalibrate the model to include the novel biomarker, pulse oximetry (SpO2); and (4) translate the miniPIERS model into a decision rule for final creation of the PIERS on the Move decision algorithm. All stages of development of the PIERS on the Move tool included input from stakeholders in low-resourced countries.
The miniPIERS model, now published in PLOS Medicine (http://bit.ly/1lhdSD9), based on demographics, symptoms and clinical signs, accurately identified women who are at greatest risk of complications from the HDP (AUC ROC 0.77 [95% CI 0.74 – 0.80]). Internal validation demonstrated minimal overfitting with an average optimism of 0.037.
An important update to the miniPIERS model was completed this year when the model was extended and recalibrated to include the novel biomarker, SpO2. Addition of SpO2 to the miniPIERS
model resulted in a 20% increase in classification accuracy of high-risk women. SpO2 of <93% was associated with a 30-fold increase in risk [95% CI 14–68] of adverse maternal outcome compared with women with SpO2 >97%. After recalibration and extension, the miniPIERS model including SpO2 (vs. not) had improved sensitivity (49.6% vs. 32.8%) at the cost of decreased specificity (96.2% vs. 91.5%) when a threshold of 25% predicted probability is used to identify the high-risk women. With SpO2, the model discriminated well with an area under the receiver operating characteristic curve of 0.781 [95% CI 0.729, 0.832]. A publication detailing the results of this analysis is in press in the Journal of Obstetrics and Gynaecology Canada.
Another major focus of the Objective 2 team this year was validation of the decision algorithm based on the miniPIERS model that is used on the PIERS on the Move (POM) mHealth application. Using an iterative review and feedback process including stakeholders from our partner low-resourced countries, decision points defined by the miniPIERS model were combined with the WHO recommendations for treatment of women with HDP to create a novel decision algorithm for population-level risk screening. This decision algorithm identified high-risk women in the miniPIERS cohort with a sensitivity of 74.1% and specificity of 51.4%. Pilot testing of this tool in South Africa demonstrated potential impact but the true impact of use of the POM tool on maternal outcome rates requires assessment through the CLIP trials. Further details of the POM project are presented separately in this annual report. Pilot assessment of use of the POM tool through the CLIP trial began this year with great success. Full details of this work are presented under Objective 3.
Now that both the miniPIERS and PIERS on the Move studies have been completed, the Objective 2 team was able to focus on dissemination of results throughout the year. In addition to the publications resulting from this work, several presentations were made at international conferences with a focus on developing new strategic partnerships that will allow expansion of the PIERS work beyond pre-eclampsia risk management. Beth presented
work related to the PIERS study and development of the POM mHealth app in Lausanne, Switzerland at the 2014 International Conference on Technologies for Development in June and at King’s College London for the BMC Evidence-based Medicine in global health meeting in July. In relation to her work on the PIERS project, Beth was also awarded a Canadian Institute of Health Research graduate student award in Winnipeg, Manitoba at the Canadian Health Science Student Federation research competition in mid-June. In addition, Peter von Dadelszen represented the PIERS team in Washington D.C. this year at the Saving Lives at Birth Round 4 Innovators meeting where he presented our idea for transition of the PIERS on the Move platform into a broader platform for assessment of risk of pregnancy complications beyond pre-eclampsia, such as postpartum hemorrhage and obstetric sepsis. At this meeting we were able to secure funding to continue this important work and expand on the success of the PIERS project.
YEAR FIVE ANTICIPATED DELIVERABLES
Year 5 goals include: publication of manuscripts (1) outlining recalibration and extension of the miniPIERS model to include SpO2, (2) describing risk factors for stillbirth and perinatal death in the miniPIERS cohort, and (3) describing the impact of various model development steps to overfitting of clinical prediction models; completion of pilot assessment of the miniPIERS model implemented through the CLIP Pilot trials in Nigeria, Pakistan and India.
COMMUNITY BLOOD PRESSURE MONITORING IN RURAL AFRICA: DETECTION OF UNDERLYING PRE-ECLAMPSIA (CRADLE)Principal Investigator: Andrew Shennan
Trainee: Hannah Nathan
Collaborators: Annemarie de Greeff (South Africa);
Suellen Miller (University of San Francisco); Gerhard Frick (Microlife™)
OVERVIEW
Accurate and regular BP monitoring is a cost-effective screening tool for the early identification and management of pre-eclampsia in pregnancy. In low- and middle- income countries (LMICs), pre-eclampsia is frequently under-detected not only because attendance for antenatal care is often low, but also, due to inadequate training in how to take accurate BP measurements, and insufficient, poorly functioning equipment. Firstly, training in the use of a cheap yet technically challenging method, the traditional sphygmomanometer, is often lacking amongst health care workers staffing antenatal clinics. Secondly, there is concern over the robustness and safety of these traditional devices (those containing mercury), while the next generation aneroid instruments are frequently inaccurate through calibration drift and ideally require six-monthly re-calibration to maintain accuracy. Thirdly, the use of ‘manual’ BP devices such as these, which require auscultatory skills and the observer recording the BP from a calibrated scale is associated with user-bias resulting in inaccurate measurement. This has been attributed to terminal digit preference, wrong Korotkoff sound interpretation, threshold avoidance, and incorrect deflation speeds. Third-generation BP devices which automatically inflate the cuff and provide a digital reading, whilst circumventing some of these issues, are also unsuited for use in LMICs as they depend on an expensive power supply to drive the automatic pump, or source of batteries and have poor resistance to shock and fluctuations in temperature; most are inaccurate and worryingly underestimate the BP in hypertensive pregnancy. In addition, for all devices, staff may not always be trained in the interpretation of the BP readings, especially in those settings where it is seldom taken due to lack of equipment.
Accurate BP measurement is not only vital for detecting and monitoring pre-eclampsia and other hypertensive disorders of pregnancy, but also other life threatening maternal conditions such as PPH (as well as intrapartum and antepartum haemorrhage) and sepsis. PPH, sepsis and pre-eclampsia are the leading direct causes of maternal death and morbidity in LMICs. Visual estimation of blood loss at PPH is often unreliable, as is the relationship of blood loss to maternal symptoms. Hypovolaemic shock may be complicated by anaemia, resulting in a greater degree of compromise related to blood loss. Furthermore blood loss may be concealed (e.g. placental abruption). Given that PPH can lead to death within two hours, early recognition is essential. A community 1312
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the woman is symptomatic or until the blood loss reaches a defined level, would quickly alert the community health care provider (cHCP) to severe maternal compromise, and potentially prompt community-based initiation of treatment of the patient (e.g. intravenous (i.v.) fluids and antibiotics) and/or emergency transfer for definitive care.
The CRADLE project
The King’s College London CRADLE research group, in collaboration with Microlife, has previously developed a semi-automated BP device (Microlife 3AS1–2) specifically for use in LMICs. It can be manufactured at low cost (<$20/piece) and the manual inflation means that battery supply is only used to power the display showing the BP readings. We clinically validated this device for use in pregnancy (including pre-eclampsia) in a low resource setting, and piloted its clinical use in a feasibility study (phase one of CRADLE) in sub-Saharan Africa for detection of pre-eclampsia (Tanzania, Zambia and Zimbabwe). In the pre- and post-intervention study we demonstrated that the BP device was accurate, easy to use and acceptable to health workers in rural antenatal care clinics. The introduction of the device into peripheral clinics increased referrals from the community to hospital facility for suspected pre-eclampsia. On the basis of this work, our group were successful in obtaining generous further funding from the Bill & Melinda Gates Foundation Grand Challenges Explorations for phase two of CRADLE.
Picture 4: Handheld automated blood pressure monitor (N3 BP device).
The primary objective of phase two of the CRADLE project is to develop an accurate and tested low-cost solution to improve
antenatal detection of pre-eclampsia, and shock associated with postpartum haemorrhage (PPH) and sepsis, by adapting existing tools for BP measurement for use by frontline health care providers working at a community level and in first-level clinics, who are best placed to both access pregnant women and initiate life-saving interventions. Equipping frontline health workers with novel technology such as this, as well as provision of basic training in its use, enhances their capabilities and performance. Once widely implemented in LMICs, the availability of BP measurements will facilitate referrals of high-risk women to secondary level centres and thereby has potential to improve pregnancy outcome for both the mother and infant.
YEAR FOUR PROGRESS
Our research group has further modified the Microlife 3AS1–2 BP device, ensuring suitability in a community low-resource setting. The modified CRADLE BP device now comprises a micro-USB port and sealed rechargeable lithium battery pack, allowing charging through generic mobile phone chargers. A traffic-light early warning system has been incorporated into the device, to alert users to abnormalities in blood pressure. For the purposes of the CLIP trial in Nigeria, the traffic light system will alert community healthcare providers to thresholds of hypertension (defined in the CLIP protocol). Options for the device display together with traffic light flashing sequence was qualitatively evaluated and the most widely understood display and sequence was chosen for the final device.
Understanding that obstetric haemorrhage is the leading cause of maternal death worldwide, our group has further developed the device to alert users to changes in observations secondary to hypovolaemic shock, as well as hypertension. We have retrospectively analysed datasets of women with postpartum haemorrhage (one dataset in the UK and another large dataset of women in four African low-resource settings, in collaboration with Suellen Miller and the Safe Motherhood Program, UCSF) to evaluate the predictive value of conventional vital signs (including low BP and high pulse) as well as Shock Index, the ratio of pulse to systolic BP. Shock Index was shown to be a more consistent predictor of adverse clinical outcomes than conventional vital signs; two thresholds of Shock Index were determined according to increased risk of adverse outcome, to correspond to amber and red lights within the traffic light system (study published in the Women’s Global Health addition of BJOG). As well as the pre-defined hypertension thresholds used in the CLIP study, we will be prospectively validating the Shock Index thresholds at an institutional level at three sites in South Africa.
Following on from the Shock Index prediction study, we retrospectively analysed a large dataset of UK women in the immediate postpartum period with uncomplicated deliveries to determine the normal range of Shock Index, as well as conventional vital signs. These results supported our previous Shock Index prediction study results and will help guide healthcare providers utilising Shock Index as a trigger for action.
As well as ensuring the Microlife 3AS1–2 is accurate in pregnancy, including pre-eclampsia (validation study published in BPMJ [in press]), the CRADLE team, in collaboration with Annemarie de Greeff, successfully validated the device in pregnant women with low blood pressure. This is the first validation of an automated BP device at low blood pressures. In a separate validation study, our group evaluated the impact of inappropriate cuffing (over- and under-cuffing) using the Microlife 3AS1–2 BP device in pregnant women. Our results reinforced the importance of using the appropriately sized cuff when measuring blood pressure to ensure accuracy.
Picture 5: Handheld automated blood pressure monitor (N3 BP device).
YEAR FIVE ANTICIPATED DELIVERABLES
In collaboration with Microlife, CRADLE will be providing the BP devices for community healthcare providers at all cluster sites in the CLIP Definitive cRCT. In Mozambique, India and Pakistan the original Microlife 3AS1–2 BP device will be provided, whereas in Nigeria the modified CRADLE device (with hypertensive traffic light system) will be provided. During this clinical implementation, quantitative CRADLE-specific outcomes will be collected during the two-year CLIP study, to evaluate the impact of the introduction of the device on routine antenatal care, diagnosis of pre-eclampsia and rates of adverse clinical outcome. The acceptability, usability and feasibility of the device for use by community healthcare providers will also be assessed, through interviews and observational sessions at 3 months and 12 months from the start of the CLIP definitive trial.
Also in year five, the CRADLE research group will be running the one-year Clinical Practice Evaluation of the modified device
for the detection of pre-eclampsia and shock at an institutional level at three South African sites. The purpose of this evaluation will be to (1) quantitatively validate the pre-defined hypertension and Shock Index traffic light thresholds according to risk of adverse clinical outcomes and (2) qualitatively assess the acceptability, usability and feasibility of the BP device (together with traffic light early warning system) for use by institutional health care providers. Alongside the clinical practice evaluation, we will also be building on our Shock Index knowledge base through a prospective observational study of Shock Index and conventional observations in the immediate postpartum period in women with uncomplicated deliveries in two hospitals in South Africa (and ensuring accuracy of observations by using the Microlife 3AS1–2 BP device).
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REVIEWS Principal Investigator: Laura Magee
Trainee: Tabassum Firoz
OVERVIEW
Maternal and perinatal mortality and morbidity audits will be performed at both households and facilities by a trained surveillance team within the CLIP trial. The timing of these audits is individualised to the specific country: quarterly in Pakistan, six-monthly in Nigeria and Mozambique and within 6 weeks of delivery in India. Data collection will begin with traditional hard copy forms in all sites but will transition to a mobile platform in Nigeria, Mozambique and Pakistan. In intervention clusters in all countries, community health care providers (cHCPs) will be using mobile phones to collect data and administer the PIERS on the Move diagnostic algorithm, which will also collect information on adverse maternal outcomes.
Over the last year, the definitions, indicators and tools for capturing maternal/perinatal mortality and morbidity have been refined and finalised for the CLIP cRCT.
MATERNAL MORTALITY, AND MATERNAL MORBIDITY (IN CONJUNCTION WITH THE WHO MATERNAL MORBIDITY WORKING GROUP)Principal Investigator: Lale Say (WHO MMWG)
& Laura Magee (maternal death)
Funding: Bill & Melinda Gates Foundation,
with World Health Organization
MATERNAL MORTALITY & SEVERE ACUTE MATERNAL MORTALITY
Maternal Mortality
Definition
For the CLIP cRCT, maternal mortality is defined as the number of deaths during pregnancy or within 42 days of pregnancy (in women aged 10–49) per 100,000 identified pregnancies. Although the World Health Organization (WHO) definition of reproductive age women is 15–29 years, CLIP is suggesting 10 years as the lower limit since a proportion of girls may be married by 10 years old in some study sites.
The classic WHO definition of the maternal mortality ratio (MMR) is events per 100,000 live births. A different denominator has been chosen for the reporting of maternal mortality and morbidity for the CLIP cRCT, than that classically used by the WHO. The reason for this is that it is hoped that the CLIP intervention will reduce the burden of stillbirth in women with pre-eclampsia. Therefore, even in the absence of any absolute change in maternal adverse event rates (per pregnancy), the MMR per 100,000 live births could fall artificially as the proportion of live born infants increases. For the CLIP cRCT, the term “maternal death rate (MDR)” will be used. Classically defined MMR will be reported.
Method
When a maternal death is identified, a verbal autopsy will be initiated to identify the cause of death. When possible, data obtained from the verbal autopsy will be triangulated with data obtained from health care records. The 2012 WHO Verbal Autopsy questionnaire will be used, using the inter VA application.
Social autopsies will be undertaken to identify and understand the social, behavioural, and health systems contributors to maternal deaths and major morbidities (see below). The themes relating to delays in identification, arranging transport and
seeking treatment were drawn from the MAPEDIR (Maternal and Perinatal Death Inquiry Response) tool.
Maternal morbidity
The main challenge has been around selecting appropriate indicators for maternal morbidity and their definitions, particularly, at the community level. The literature has shown that self-reported maternal morbidity is often inaccurate and inconsistent. Therefore, indicators were selected that would be both clinically meaningful and significant to the woman in order to reduce recall bias. In developing definitions for the indicators, the challenge was to remain simple, objective, context specific and cognisant of resource implications. This process has also highlighted the need for an assessment tool that would be more reliable than self-reporting of maternal morbidity.
PRE-EMPT continues to participate in the WHO Maternal Morbidity Working Group (MMWG). A framework, the maternal morbidity matrix, has been developed. Using the definition, a list of potential maternal conditions has been identified and categorised in a fashion similar to the ICD-10 Application to Maternal Mortality. As this framework is focussed on community and primary healthcare level assessment, the objective is to identify morbidity within the broad categories. Each category has accompanying symptoms, signs, investigations and management strategies. Wherever possible, evidence has been used to inform the identification criteria. To understand the impact of morbidity (and to capture morbidity when the identification criteria cannot), several dimensions of functional disability will be used. A maternal history section will accompany these two components and will contain information about risk factors, obstetric and medical history. We plan to use and validate the tool developed by the MMWG to capture maternal morbidity in the community setting. Alas, we plan to build on this tool by developing a probabilistic model to diagnose maternal morbidity.
Definitions
The definitions for maternal morbidity have been derived from the WHO Near Miss Approach for Maternal Health, as well as from relevant literature reviews and current practices at CLIP study sites. The aim was to select indicators that reflect pre-eclampsia related morbidity in addition to the other leading causes of maternal mortality (sepsis, postpartum haemorrhage and obstructed labour).
Severe maternal morbidity is defined as the number of women with one/more life-threatening complications of pregnancy during pregnancy or within 42 days of pregnancy (or last contact day if contact not maintained to 42 days) per 100,000 identified pregnancies.
The current indicators of severe maternal morbidity in the CLIP trial are:
• Serious end-organ complications of pre-eclampsia:
• Eclampsia: occurrence of generalised convulsions during pregnancy, labour or within 42 days of delivery in the absence of epilepsy or another condition predisposing to convulsions
• Stroke: hemiparesis and/or blindness developed during pregnancy or in the 42 days postpartum lasting greater than 48 hours
• Coma: prolonged unconsciousness ≥12 hours
• Antepartum haemorrhage: vaginal bleeding ≥ 15 mL with or without pain before the onset of labour
• Disseminated intravascular coagulation (DIC): abnormal bleeding from mucosa (mouth and/or ears)
Other major causes of maternal mortality:
• Obstetric sepsis: In the community, defined as fever and one of: abdominal/uterine tenderness, foul smelling vaginal discharge/lochia, productive cough and shortness of breath, dysuria or flank pain, headache and neck stiffness. In the facility, defined as presence of fever (>38°C), a confirmed or suspected infection (e.g., chorioamnionitis, septic abortion, endometritis, pneumonia) and at least one of the following: heart rate >90/min, respiratory rate >20/min, leukopoenia (total leukocyte count [TLC] <4 x 109/L) or leukocytosis (TLC >12 x 109/L)
• Vesicovaginal or rectovaginal fistula: continuous loss of urine and/or faeces after delivery
Life-saving interventions:
• Cardiopulmonary resuscitation: a set of emergency procedures including chest compressions and lung-ventilation applied in cardiac arrest victims
• Dialysis: haemodialysis and/or peritoneal dialysis
• Mechanical ventilation (other than for Caesarean section): intubation and ventilation not related to anaesthesia
• Blood transfusion: ≥1 unit
• Interventions for major postpartum haemorrhage: brace sutures, external and internal uterine compression, anti-shock garment use, internal iliac artery ligation and/or hysterectomy with or without transfusion
To understand the impact of morbidity on the woman’s wellbeing, functional disability has been included as an “other” outcome. Functional disability defined as physical inability to perform usual daily duties at specific points in time during the
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PERINATAL MORTALITY AND SEVERE MORBIDITY
Perinatal and neonatal mortality
The primary outcome for CLIP will include perinatal and late neonatal death. Perinatal death is defined as stillbirth [≥20+0 and/or ≥500g] and/ or early neonatal mortality [days 0–7 of postnatal life]. Late neonatal mortality is defined as death from days 8–28 of postnatal life. The denominator will be per 100,000 identified pregnancies in keeping with our rationale previously described.
As with maternal mortality, verbal and social autopsies for perinatal and neonatal deaths will be conducted. The WHO 2012 Verbal Autopsy questionnaire (death of a child under 4 weeks) and the MAPEDIR questions described above will be used as the tools to audit perinatal mortality.
Neonatal morbidity
There are indicators of neonatal morbidity occurring between 0–28 days of postnatal life and determined at both the community and facility levels. The denominator for neonatal morbidity is per 1000 identified pregnancies. The indicators and their corresponding questions were drawn from the Child Health Epidemiology Reference Group (CHERG) verbal autopsy and cross-referenced with the WHO Verbal Autopsy questionnaire.
The following are the primary perinatal/neonatal morbidities:
• Feeding difficulty
• Breathing difficulty
• Seizure
• Lethargy
• Coma
• Fever
• Hypothermia
• Umbilical cord infection
• Skin infection
• Bleeding
• Jaundice
• Vomiting/diarrhoea
mHealth TO SUPPORT PREGNANCY HEALTH MONITORING IN CLIP AND BEYOND
PIERS ON THE MOVE (POM) Co-PIs: Mark Ansermino, Guy Dumont & Peter von Dadelszen
OVERVIEW
The PIERS on the Move (POM) project was initiated to expand on the work of the miniPIERS project through creation of an innovative and cost-effective mobile health (mHealth) application for pre-eclampsia triage. This tool was designed as a technological solution to the shortage of health workers trained to manage women with HDP. The POM tool integrates a decision point defined by the miniPIERS predictive model with other clinically relevant decision points, most notably low SpO2 measured by the Phone Oximeter, and the WHO recommendations for treatment of women with the HDP. The POM tool guides a minimally-trained health worker through an antenatal assessment, prompting them to measure the woman’s blood pressure and blood oxygen saturation and to ask about important symptoms and then provides recommendations for further treatment or referral based on the clinical measures recorded.
YEAR FOUR PROGRESS
This year saw the completion of the PIERS on the Move seed grant-funded project in South Africa. A publication detailing the final results of all usability testing with South African midwives has now been submitted for publication. A second publication resulting from this study is described above in the miniPIERS update and resulted in recalibration and extension of the miniPIERS model to include SpO2 and is now accepted for publication. A third manuscript was published in late 2014 in the IEEE Journal of Biomedical and Health Informatics on the technical development of the POM app.
The major focus of the POM team this year was to finalise revisions to the POM tool for use in the CLIP Pilot trials. This process involved several iterations of review and feedback to UBC by the CLIP trial teams in each country. The result of this was development of four versions of the POM application for CLIP; one specific to each countries health care setting and language needs. These applications allow for the completion of CLIP visits and collection of a core set of data required to complete the trial but are unique in several aspects, reflecting the differences in the health system and workers in each CLIP country. For example, in India where both ASHAs and ANMs will be using the application, we have developed two versions of the application. The ASHA version is as simple and streamlined as possible, whereas the ANM version includes additional
questions around more complex clinical tasks such as provision of i.m. magnesium sulphate injections and adverse event follow-up.
Piloting of these tools in Nigeria, Pakistan and India is described in the Objective 3 update later in this report.
Picture 6: An ASHA worker in India using the POM app during a training session.
Picture 7: A community health worker (CHW) in Pakistan using the POM app.
In all cases feedback from the field staff has been positive and the health workers have demonstrated the capacity to learn and use the POM tool effectively. There have now been more than 4298 women evaluated with the CLIP POM app in all three pilot trials! The Pilot trials provide excellent opportunities for refinement of the application itself. Based on feedback from the field and review of the initial 6 months of pilot trial data we have revised the application in a few notable ways. First, health workers were often missing responses regarding acceptance of treatment and referral recommendations so this page of the application has been redesigned to be more intuitive. Secondly, the date wheels continued to pose a problem for usability in the field so these have been redesigned to work more smoothly. Finally, it was noted that in most countries proteinuria is measured at all antenatal visits, previously the app only asked about dipstick results on the first visit and any subsequent visit where high blood pressure was identified. To ensure the tool reflects on the ground practice the proteinuria module is now accessible at every study visit.
An important update from the POM team was the successful application for funding through Round 4 of the Saving Lives at Birth Grant competition. Peter von Dadelszen represented the PIERS on the Move team in Washington D.C. this year at the Saving Lives at Birth Round 4 Innovators meeting where he presented our idea for transition of the PIERS on the Move platform into a broader platform for assessment of risk of pregnancy complications beyond pre-eclampsia, such as postpartum haemorrhage, obstructed labour and obstetric sepsis.
YEAR FIVE ANTICIPATED DELIVERABLES
In the coming year the main focus of the team will be to work on development and validation of clinical prediction models for other areas of maternal and child health and expansion of the scope of the POM tool for improved scalability.
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MOTHERS Co-Principal Investigators: Tabassum Firoz & Tatenda Makanga
Mozambique leaders: Khátia Munguambe, Esperança Sevene
& Charfudin Sacoor
Funding: Grand Challenges Canada
OVERVIEW
Mapping Outcomes for Mothers (MOM) was awarded a Stars in Global Health grant by Grand Challenges Canada to support “bold ideas with big impact.” The project is set in Maputo and Gaza Provinces in Mozambique and aims to develop a mobile health (mHealth) application for use by community health workers to predict local maternal risk and offer recommendations to avert this risk. Underpinned by the social determinants of health framework, maternal risk will be evaluated in four dimensions: maternal characteristics, health systems and services factors, socio-economic and environmental determinants. While community level factors (such as health systems and services factors and certain social and environmental variables) will inform individual maternal risk, the project will also develop an index for community resilience (described as the ability of a community to cope in the face of significant adversity and risk).
To display an integrated picture of local maternal health risk, MOM will use geographic information systems (GIS), a uniquely integrative mix of hardware, software and analyses that enable spatial epidemiology, or the geo-visualisation of the distribution and determinants of health phenomena. This will allow policy makers to take targetted and individualised action at the community level.
Picture 8: Road leading to one of the wards in Nigeria.
Picture 9: One of the cars that provide transport support to pregnant
women during labour or any other emergency in Nigeria.
YEAR FOUR PROGRESS
Data collection has been completed. The baseline household survey has been completed in 12 clusters in Gaza and Maputo districts. Focus groups and in-depth interviews with key stakeholders (women, male decision makers, community leaders and community health workers) have been conducted in four pilot clusters and results are being analysed. Using the results from the qualitative data, the Delphi consensus group will assist in prioritising the variables for model development. The dataset will also be used to explore the role of community resilience and the spectrum of maternal outcomes (morbidity versus mortality).
Community level mapping of administrative boundaries, road networks and primary health care facilities has also been completed in the twelve clusters. The Mozambican national mapping agency, Cenacarta, has agreed to validate these data and complement them with data from their own sources where possible. These data will be used to ascribe risk and resilience to specific communities.
ANTICIPATED DELIVERABLES
By the end of the funding term (January 2015), the deliverables include the full maternal resilience model and the initial mHealth application. The model will include community and individual level variables to map risk and resilience based on geographical location. The mHealth application will be designed to allow
the community health worker to enter these variables with the aim of generating a risk profile and producing specific recommendations and community resources to mitigate risk.
The next steps are to apply for the Transition to Scale award through Grand Challenges Canada in order to perform usability testing for the application and to validate the model in other settings. It is envisioned that MOM will be used by policy makers to risk stratify communities and to strengthen health systems based on community-specific needs.
fullPIERS (PRE-ECLAMPSIA INTEGRATED ESTIMATE OF RISK): EXTERNAL VALIDATION AND RECALIBRATIONPrincipal investigator: Peter von Dadelszen
Trainees: Vivian Ukah (PhD candidate), Beth Payne (PhD
candidate, Joost Akkermans (O&G resident, Amsterdam)
Funding: Canadian Institutes of Health Research (operating
grants and KT award); European Union (through EBM
CONNECT)
OVERVIEW
The fullPIERS model was developed and internally validation in a cohort of 2023 women with pre-eclampsia admitted to tertiary perinatal units in Canada, the UK, New Zealand and Australia. With good stratification capacity and predictive performance (AUC ROC: 0.88), the fullPIERS model needs to be validated externally, and then recalibrated, using external datasets.
YEAR FOUR PROGRESS
Vivian Ukah, who is a recipient of the UBC Four Year Fellowship (FYF) is currently undertaking the external validation, recalibration and addition of a new biomarker, placental growth factor (PlGF) to the fullPIERS model, for her PhD project. Beginning with the 2012 CIHR Knowledge Translation Award to Peter von Dadelszen, additional CIHR operating grant was awarded to Peter von Dadelszen, to support this project during this past year.
External datasets relevant for this project have been identified; these include the Alere-funded PELICAN and PETRA studies, the PREP UK study, the CHIPS multicentre study and also the FINNPEC Finland data and the John Radcliffe hospital, Oxford, UK data, the latter two of which were identified from the Global Pregnancy CoLaboratory. Ethical approval and data sharing agreements are being put in place to ensure the use of these datasets. Both the PELICAN and PETRA studies have measured maternal blood levels of PlGF, which will be used to extend the original fullPIERS model to assess any improved prediction capacity of the model, for better identification of women at risk of complications from pre-eclampsia. Internal data collection at the BC Women’s Hospital is ongoing for the temporal validation of the fullPIERS model, which is also an important validation step.
A preliminary external validation of the fullPIERS model, carried out by Joost Akkermans using the Dutch PETRA (Pre-Eclampsia Trial Amsterdam) RCT showed high predictive performance (AUC ROC of 0.97). This paper has been published in the
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2014Eur J Obstet Gynecol Reprod Biol1. The fullPIERS model has
also been tested and updated in the miniPIERS dataset from
1. Predicting complications in pre-eclampsia: external validation of the fullPIERS model using the PETRA trial dataset. Akkermans J, Payne B, von Dadelszen P, Groen H, de Vries J, Magee LA, Mol BW, Ganzevoort W. Eur J Obstet Gynecol Reprod Biol 2014; 179: 58–62.
low-resourced settings, showing a moderate performance, AUC ROC of 0.77 (see figure) due to population characteristic differences (an abstract was presented as a poster at the International Society for Study of Hypertension in Pregnancy (ISSHP) World Congress 2014, New Orleans, LA, USA.
1-Speci�city
Sen
sitiv
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0.0
0.0 0.2 0.4 0.6 0.8 1.0
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0.8 lr.eta = 0.096
Model: outcome..1.yes. ~new.pred.proArea under the curve: 0.771
Variable est (s.e.)(Intercept) -2.712 (0.159)new.pred.pro 4.751 (0.503)
Sens: 78.0%Spec: 65.9%PV+: 5.3%PV-: 72.2%
Predicted Probability
Out
com
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0.0 0.2 0.4 0.6 0.8 1.0
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IdealLogistic calibrationNonparametric
Dxy 0.539C (ROC) 0.769R2 0.237D 0.141U -0.003Q 0.144Brier 0.098Intercept -0.022Slope 0.990Emax 0.007S:z -0.192S:0 0.848
Figure 2 and 3: AUC ROC and calibration performances of fullPIERS model within the miniPIERS dataset after intercept update, at 48 hours.
YEAR FIVE ANTICIPATED DELIVERABLES
Publication of potential manuscripts for the preliminary validation exercise of the fullPIERS model in a different setting using the miniPIERS data, in the context of a methodology paper, and external validation of the model using the PREP, Alere-funded PETRA and PELICAN datasets.
EMMA: EVALUATING MATERNAL AND FETAL MARKERS OF ADVERSE PLACENTAL OUTCOMES: THE EMMA STUDY AND CLINICPrincipal investigators: Peter von Dadelszen (2004–13),
Chantal Mayer & Julie Robertson (2013–ongoing)
Trainees: Samantha J Benton (PhD candidate), Genevieve
Eastabrook (PhD candidate), Pamela Calderon (O&G resident)
Funding: Canadian Institutes of Health Research (Proof of
Principle Grant); Alere International (unrestricted investigator
initiated grant); Provincial Health Services Authority (direct
clinic support)
OVERVIEW
As there is no single test that predicts pre-eclampsia (or the other placental complications of pregnancy, namely gestational hypertension, intrauterine growth restriction [IUGR], abruption, stillbirth and, probably, a substantial proportion of spontaneous preterm birth) with sufficient accuracy to be clinically useful, interest has grown around the development of multivariable models that include both clinical and laboratory predictors, available at booking and thereafter in pregnancy. Women at increased risk of pre-eclampsia may benefit from this type of risk stratification provided through a specialised clinic.
There is the potential to integrate discovery science into such a clinical activity, to develop models that include biomarkers on the cusp of being introduced into clinical care, as well as biomarkers more remote from that transition.
The EMMA Clinic, and its associated academic activity, was started in 2004, in response to a CIHR grant, with this combined remit of advising direct clinical care with extant knowledge, as well as improving future outcome prediction.
Clinical protocol
Using a consultation-only model, with very occasional retention of women in the MFM Clinic structure (primarily if suffering from early-onset IUGR), women are seen in the EMMA Clinic from as early as 15 weeks gestation. Blood for any outstanding maternal serum markers are drawn, and the results interpreted in conjunction with uterine artery Doppler findings. These findings are interpreted using a predetermined paradigm (Table).
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RISK NATURE OF PREVIOUS PET
NUMBER OF ABNORMAL MSS ANALYTES
UTERINE ARTERY DOPPLERS
ROUTINE ANTENATAL CARE PLUS
Population risk
Mild or late-onset PET 0 Normal —
Low risk
Mild or late-onset PET 1 Normal Education +
Severe or early-onset PET 0 NormalSingle follow-up growth scan in early 3rd trimester
Medium risk
Mild or late-onset PET 2 Normal Education +
Severe or early-onset PET 1 NormalSingle follow-up growth scan in early 3rd trimester +
Serial bloodwork and clinic visit every 4 weeks +
Ultrasound* from 20 weeks
High risk
Mild or late-onset pre-eclampsia
≥3 Normal Education +
Severe or early-onset PET 2 NormalSingle follow-up growth scan in early 3rd trimester +
Severe or early-onset PET 0–1
Persistent uterine artery notching or high resistance uterine artery flow at 22–26 weeks
Serial bloodwork and clinic visit every 2 weeks +
Ultrasound† from 20 weeks
* For growth, amniotic fluid index and umbilical artery Doppler monthly † For growth, amniotic fluid index and umbilical artery Doppler every two weeks
Table 1: Risk stratification for pre-eclampsia and intensity of antenatal care: EMMA Clinic, Vancouver
≥1 Major risk factor:Chronic renal disease
Anti Phospholipid Antibody Syndrome
Chronic hypertension
Diabetes with evidence of end
organ disease
Autoimmune disease with vascular
involvement
Maternal age ≥40 + nulliparity
Previous (i) severe pre-eclampsia or (ii)
IUGR resulting in delivery <34 weeks
Previous unexplained stillbirth
First or second trimester heavy
menstrual-like bleeding
Fetal 2nd trimester echogenic bowel
≥3 minor risk factors:Nulliparity
Maternal age <20 or >35
BMI <20 or >35
IVF pregnancy
Pre-existing diabetes
Pregnancy interval <6 or >60months
Any previous pre-eclampsia or IUGR
Smoking ≥5 cigarettes per day
Single abnormal maternal serum analyte
PAPP-A ≤ 0.15 MoM
uE3 ≤ 0.40 MoM
AFP ≥ 2.5 MoM
hCG ≥ 4.0 MoM
Inhibin A ≥ 3.0 MoM
ANTENATAL RISK ASSESSMENT FOR PLACENTALLY-MEDIATED PREGNANCY COMPLICATIONS
Abnormal maternal serum marker:• 2 abnormal analytes
PAPP-A ≤ 0.15 MoM
uE3 ≤ 0.40 MoM
AFP ≥ 2.5 MoM
hCG ≥ 4.0 MoM
Inhibin A ≥ 3.0 MoM
or
• 1 severely abnormal analyte
AFP ≥ 3.5 MoM
hCG ≥ 4.5 MoM
Inhibin A ≥ 4.0 MoM
Start ASA 81mg OD if ≤ 16 weeks GAEligible for BCW EMMA Clinic consultation
(attach risk assessment form to MFM referral)
Patient informationName:____________________________DOB:_____________________________MSP:_____________________________
Referring MD/MW:___________________Phone #_____________________________FAX #_______________________________
Date: ________________________________GA:___________ EDD:__________________G:_____ T:_____ P:_____ A:_____ L:_____
Figure 4: The current EMMA Clinic referral criteria are summarised in the referrla form.
Building on the experience and protocols of the Silver Star Clinic, John Radcliffe Hospital, Oxford, UK, women stratified to differing levels of risk are entered into stratified follow-up. Caregivers for women in the high risk stratum (≥60% risk of placental complications) receive a suggestion to initiate fortnightly follow-up that includes serial growth, fluid and umbilical artery ultrasound scans and blood work to exclude pre-clinical pre-eclampsia. Women in the intermediate risk group (30–59% risk) are advised to receive 4-weekly clinical, ultrasound and blood work assessment, while EMMA Clinic-eligible women determined to be at lower risk (<30%) are advised to receive a single additional growth ultrasound in the early third trimester.
With clinical data on approximately 800 women who have attended the clinic and for whom we have follow-up information until delivery, we are assessing the performance of the clinic in terms of accuracy of risk stratification, and the independent performance of clinical, ultrasound and laboratory assessments within a multivariable model. In addition, with pre-disease samples for approximately 200 women, we are assessing the roles of a series of hypothesis-generated biomarkers in this setting.
Results
Interim results show that risk stratification is possible in this cohort of higher risk women, and that outcomes vary by risk stratum. Also, we are assessing the outcomes for this cohort of women compared with non-attenders with similar risk factors through collaboration with Drs Amy Metcalfe, KS Joseph and Sylvie Langlois.
In addition, we have assessed the prediction performance of a series of biomarkers within this enriched cohort, and determined that some biomarkers have additional stratification value compared with more established risk stratification criteria.
Year Five Anticipated Deliverables
Publication of a series of clinical and translational biology papers related to the EMMA Clinic cohort. We anticipate at least five publications will result from this activity.
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2014CIPHER (COLLABORATIVE
INTEGRATED PREGNANCY HIGH-DEPENDENCY ESTIMATE OF RISK)
Principal Investigator: Peter von Dadelszen
Trainee: Helen Ryan
Funding: Canadian Institutes of Health Research (Pilot
Funding)
OVERVIEW
Maternal intensive care unit (ICU) admissions follow both obstetric and non-obstetric complications in pregnancy. 0.25–1.5% of hospital admissions during pregnancy will require admission to the ICU. About two-thirds of these admissions are due to obstetric causes (e.g. haemorrhage and pre-eclampsia) and one-third is due to maternal medical or surgical complications. Pregnant women with underlying medical conditions are over-represented in maternal mortality and severe morbidity statistics.
A number of critical care outcome prediction models exist in ICU to predict hospital mortality by incorporating measures of physiologic derangement and co-morbidities. The most commonly used models are the Acute Physiology and Chronic Health Evaluation (APACHE) and the Simplified Acute Physiology Score (SAPS). Their use in obstetric populations admitted to ICU for obstetric reasons to predict hospital mortality has a tendency to overestimate mortality.
Pregnancy and the postpartum state have unique physiology. Maternal cardiac output, respiratory rate and heart rate increase in pregnancy. Equally, maternal “normal range” blood values are altered in pregnancy, with lower levels of creatinine, haematocrit and urea. No outcome ICU prediction models have been designed specifically for use in obstetric patients. We aim to build on the expertise and experience in clinical prediction modeling from PIERS and develop a clinical prediction model that is applicable to any cause of maternal morbidity or mortality.
The identification of variables that predict outcome in pregnant or recently delivered women admitted to the ICU is the first step in the development of a new clinical prediction model for obstetric patients in the ICU. Such a tool will assist in providing more appropriate management to those that require it most.
Aim
To develop and evaluate a predictor of risk of severe maternal morbidity or mortality for pregnant or recently delivered women in ICU: The Collaborative Integrated Pregnancy High-dependency
Estimate of Risk (CIPHER). This study is being carried out in a number of tertiary care hospitals worldwide looking at ICU data. Secondary aims are to assess perinatal outcome and to compare performance of CIPHER against existing critical care prediction models.
Outcome
The primary outcome for the study is one/more of death, greater than 3 organ failures or prolonged duration of organ support (>7 days). Perinatal outcome will be measured as a secondary outcome.
YEAR 4 PROGRESS
We have collected over 850 CIPHER Cases across 14 sites globally. Data collection is currently underway in the following sites, and is anticipated to be completed by December 2014.
• Vancouver, Canada
• Toronto, Canada
• New York, USA
• Buenos Aires x 2 sites, Argentina
• Campinas, Brazil
• AMC, the Netherlands
• Shanghai, China
• Melbourne, Australia
• Amman, Jordan
• Malatya, Turkey
• Dublin, Ireland
• Karachi x 2 sites, Pakistan
Preliminary analysis has shown four variables that were the strongest predictors of combined outcome from the CIPHER model:
1. Urea bicarbonate levels
2. Minimum heart rate
3. Maximum temperature
4. Activated Partial Thromboplastin Time
The second analysis took place in October 2014 with the results being finalised in November 2014. Final analysis is planned to begin in January 2015, followed by manuscript writing and circulation of the findings.
YEAR 5 ANTICIPATED DELIVERABLES:
A systematic review of the accuracy of existing critical care prediction models at predicting death in pregnant and postpartum women is currently underway. This review has been registered with PROSPERO and data abstraction has begun. We hope to complete data abstraction and data analysis by December 2014. We anticipate that the data collection for CIPHER will be completed in all participating sites by December 2014. The data analysis will continue through December 2014 with model development completed by July 2015.
MEOWS (MODIFIED EARLY OBSTETRIC WARNING SYSTEM)Principal Investigator: Peter von Dadelszen
Trainee: Helen Ryan
Funding: Canadian Institutes of Health Research (Pilot Funding)
OVERVIEW
Early warning systems (EWS), also known as physiological track and trigger systems, are clinical prediction models that involve serial observation of vital signs (“track”) with criteria (“trigger”) to be used by caregivers to identify quickly a sick patient who is at risk for adverse outcome. EWS are used in general medicine. However, at present, there is no universally validated EWS for pregnant women. An obstetric EWS was strongly recommended by the UK Confidential Enquiries into Maternal and Child Health (CEMACH). Based on obstetric EWS from nine UK hospitals, the MEOWS (Modified Early Obstetric Warning System) model was proposed incorporating elements from each EWS. MEOWS involves a sheet which tracks 15 vital signs over time for each patient. Thresholds are given for a borderline or dangerous reading: two borderline or one dangerous value at one time indicates that the woman is at risk. The MEOWS chart is simple to use and potentially applicable across many settings. However, an EWS should be an accurate predictor: if an EWS has poor sensitivity, then sick patients will be missed; if poor specificity, then resources will be directed to patients not needing them. An EWS may change management, but not necessarily for the better if it is inaccurate. Therefore, validation of the predictive value and the physiological parameters of MEOWS is necessary.
As a sub-study to the CIPHER study, we are collecting data for the 24 hours prior to ICU admission on women admitted to ICU in Vancouver. Each of these cases will be compared to three pregnant / recently delivered control cases, also admitted to hospital for a duration of >24 hours. This information will be used to validate the Modified Early Obstetric Warning System.
Aim
To validate MEOWS using Canadian data for pregnant, or recently pregnant, hospitalised women.
Outcome
To determine whether MEOWS can predict the primary outcome of maternal ICU admission, any organ failure, or death in a Canadian population. Organ failure and death are included because indications for ICU admission may vary between centres and some women may become ill or die before they get to the ICU.
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2014YEAR FIVE ANTICIPATED DELIVERABLES
A literature review of physiological track and trigger systems for use in obstetric patients will be completed by the end of this year. Analyses of case and control data collected from BC Women’s and St Paul’s Hospitals is currently underway and validation of the MEOWS score will be completed by early 2015.
ECONOMIC EVALUATION OF THE CLIP TRIALPrincipal Investigators: Peter von Dadelszen & Craig Mitton
PhD Student: Asif Raza Khowaja
OVERVIEW
Economic evaluation of the CLIP trial will be pivotal role in informing policy decisions about the allocation of resources for the post-trial programme scale-up in the selected countries. We hypothesize that the CLIP package of interventions, compared with routine pregnancy care, will be cost-effective in reducing combined maternal and perinatal mortality and severe morbidity. Using a societal perspective, we are interested in determining the costs to the health care system, and costs to families of the pregnant women who are identified at risk of high blood pressure during pregnancy in the intervention and control clusters. In addition, qualitative focus groups will be conducted with pregnant women, male decision makers, health care providers at community/referral health facilities, and health decision/policy maker onsite, specifically those involved in the implementation of the CLIP trial. This integrated methodological approach will inform the design of our costing model, allow us to conduct a cost-effectiveness analysis, and support interpretation of economic analysis for decision makers who are considering evidence of economic value along with the effectiveness of the CLIP package of interventions. Economic evaluation of the CLIP trial will take place in two CLIP countries (i.e., Pakistan and Mozambique) representing each of the South Asian and African regions.
Picture 10: CLIP pilot trial surveillance officers conducting a visit in a household in Nigeria to collect data.
YEAR FOUR PROGRESS
In the past year, the research protocol was developed and letters of support from site investigators and stakeholders from the ministries of health were obtained. Research grant applications were submitted to Canadian Institute of Health and Research (CIHR), and Global Health Research Initiative (GHRI), which were unsuccessful. Health economics data collection tools (i.e., health facility resource utilization and out-of-pocket costs questionnaires) were designed, translated into local languages and sequentially embedded into the CLIP trial surveillance forms with intuitive skip logic. Furthermore, qualitative data collection tools (i.e. focus group guides) were prepared and translated into local languages to supplement the health economics analysis. Lastly, the ethics applications were submitted to the ethics agencies in UBC, Vancouver, AKU, Pakistan, and UEM, Mozambique.
YEAR 5 ANTICIPATED DELIVERABLES
Field staff (data collectors) will be trained on health economics questionnaires, and data will be collected through the CLIP trial surveillance. Qualitative focus groups will be conducted and analysed to inform the design of costing model. In addition, health facility resource utilization and out-of-pocket cost related information will be prospectively collected alongside the definitive CLIP trial regular surveillance. The referral health facilities (inclusive of public and private institutions) will be surveyed to collect information about unit-pricing for in-patient and out-patient maternal/perinatal health services in the intervention and control clusters. The district Health Department will be used as a liaison to collect information about program costs (i.e., salary, benefits and transport) of community health care providers. Lastly, an interim analysis will be performed to frame the decision analytic tree, with costs and outcome model inputs from intervention and control clusters.
PLGF IN IUGR (PLACENTAL GROWTH FACTOR IN INTRAUTERINE GROWTH RESTRICTION) STUDYCo-Principal Investigators: Lesley McCowan, the late Andrée
Gruslin, Peter von Dadelszen
Trainee: Samantha Benton, PhD
Overview
This study is being conducted to collect blood samples from pregnant women to evaluate the utility of biomarkers for the diagnosis of intrauterine growth restriction (IUGR). Currently, it is difficult for clinicians to discriminate between fetuses with IUGR and those who are naturally small (low-risk pregnancy) as both appear the same on ultrasound scans. The placenta is collected after delivery to confirm if the women has IUGR (dysfunctional placenta) or if the baby is naturally small (normal placenta). Differences in the levels of these biomarkers between these groups may provide clinicians will an additional tool to reliably identify IUGR.
The purpose of this study is to collect blood samples from pregnant women with small fetuses to evaluate the utility of biomarkers found in maternal circulation as diagnostic tools to discriminate intrauterine growth restriction (IUGR). Placentas from enrolled women will be collected for examination to confirm the presence of IUGR. We will also store remaining blood samples for future biomarker research related to IUGR. The primary hypothesis is that our candidate biomarkers (placental growth factor, soluble fms-like tyrosine kinase, soluble endoglin) will be an effective aid to the diagnosis of intrauterine growth restriction in women with small fetuses. The secondary hypothesis is that future biomarkers found in maternal circulation will be identified and evaluated alone or in combination with our candidate markers to improve the diagnosis of IUGR in women with small fetuses.
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Picture 11: Samantha Benton conducting PlGF analysis on blood samples using the Alere device.
Study Sites
This is a multi-centre, prospective, sample collection cohort study. The study is taking place at BC Women’s Hospital, the Ottawa General Hopsital (Ottawa, Ontario), and at St. Thomas’s Hospital (London, England), and National Woman’s Hospital, Auckland, New Zealand. The New Zealand collaboration was identified through the Global Pregnancy CoLaboratory (Objective 4). Blood samples are collected from women with small fetuses as indicated by decreased symphysis-fundal height, estimated fetal weight <10 percentile for gestational age and/or fetal abdominal circumference <10th percentile for gestational age on ultrasound. Samples will be batch assayed for angiogenic factors. The results of the angiogenic factor testing will be blinded to the medical personnel involved in care of the woman during the study and will not impact her medical management in any way. In addition to the blood sample, the placenta from each enrolled woman will be collected at the time of delivery. Placentas are macroscopically examined and tissue will be collected and processed for microscopic examination to evaluate the presence of placental dysfunction to define the outcome of IUGR versus a constitutionally small fetuses. Sections of placental tissue will also be analysed in a basic science laboratory using immunohistochemistry and image analysis software to quantify the level of placental dysfunction present.
PlGF and IUGR
Amongst fetuses with suspected intrauterine growth restriction (IUGR; based on abdominal circumference (AC) or estimated
fetal weight (EFW) <10th percentile on antenatal ultrasound), the majority (~65%) will be constitutionally small while ~25% will have IUGR due to placental dysfunction. Abnormal placentation in early pregnancy is believed to precipitate dysfunction in later gestation when fetal demands exceed the exchange capacity of the placenta, potentially leading to compromised fetal growth. The ability to identify placental dysfunction antenatally would improve clinical management of these fetuses and allow for the allocation of resources to the truly at-risk fetus. In addition, evidence-based identification of the constitutionally small fetus, and resulting reassurance, will reduce the number of newborns delivered with iatrogenic late prematurity resulting from surveillance fatigue.
Angiogenic factors may provide a novel clinical tool to antenatally differentiate between fetuses with placental dysfunction, and who are consequently growth restricted, and those fetuses who are constitutionally small. In our pilot study, placental growth factor (PlGF) discriminated between these groups with high sensitivity and specificity when placental IUGR was confirmed by the presence of placental pathology (Benton et al. Am J Obstet Gynecol 2012). As an extension of this pilot work, we are evaluating the utility of maternal PlGF to identify fetuses with placenta IUGR in a large cohort of fetuses with AC or EFW <10th percentile for gestational age. We postulate that PlGF will differentiate pregnancies complicated by placental IUGR fetuses, confirmed by presence of placental lesions associated with placental dysfunction, from pregnancies with constitutionally small fetuses.
In addition to determining potential clinical utility of PlGF in identifying fetuses with placental IUGR, we are performing quantitative analyses of placental morphology on a subset of the placentae collected as part of the study to better define the relationship between circulating PlGF and abnormal placental morphology. To date, the correlations between maternal angiogenic factor concentrations and placental morphology in IUGR are limited. A better understanding of the association between these markers and placental lesions may help to further elucidate the pathological processes these markers are reflecting in pregnancy complications.
Blood samples have been collected from a cohort of women with singleton pregnancies at the time of an EFW or AC <10th percentile for gestational age (GA) on ultrasound between 20–40 weeks. PlGF has been quantified using the Triage® PlGF assay (Alere). Women are grouped based on PlGF concentration at sampling (<5th or ≥5th percentile for GA based on cut-offs derived from uncomplicated pregnancies). The outcome of interest is a placental pathology grading of ≥2 for lesions of maternal malperfusion, villous maldevelopment, non-infectious villitis, perivillous fibrin deposition, interplacental hematoma and placental weight. Each lesion is graded from 0–3 (absent-severe) by an experienced pathologist, blinded to pregnancy outcome and PlGF levels, based on Redline’s scheme.
We are using a 2x2 contingency table to calculate the relative risk for the placental outcome by either PlGF <5th or ≥5th
percentile at sampling. Sensitivity and specificity are being calculated with 95% CIs.
To date, of the 73 women recruited and with complete data, 29 (40%) women had a PlGF <5th percentile for GA at the time of sampling. Of these, 20 (69%) had the placental outcome. 44 (60%) women had PlGF ≥5th percentile at sampling and one of these women (2%) had the placental outcome (RR= 30.3 [95%
CI: 4.3, 214.0], P<0.0001). A PlGF <5th percentile (positive test) identified the placental outcome with 95% [76, 100] sensitivity and 83% [70, 92] specificity (Table).
Our interim conclusion is that PlGF may provide an important additional method to identify placental dysfunction antenatally in pregnancies with suspected IUGR.
Table 2: Performance of a positive PlGF test to identify the placental outcome.
SENSITIVITY SPECIFICITY PPV NPV +LR -LR
[95% CI] [95% CI] [95% CI] [95% CI] [95% CI] [95% CI]
95 [76, 100] 83 [70, 92] 69 [49, 85] 98 [88, 100] 5.5 [3.0, 10.0] 0.06 [0.009, 0.4]
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2014REMEMBERING ANDRÉE GRUSLIN
Written by: Elizabeth Payne ([email protected])
Published online on Ottawa Citizen (http://bit.ly/1zMWw7o) on June 18, 2014 Last
Updated: July 2, 2014 5:37 PM EST
Dr. Andrée Gruslin was an internationally renowned researcher whose passion for her work was fuelled by what she learned at the bedsides of her high-risk pregnant patients.
Her death last month from cancer at the age of 49 has left colleagues at The Ottawa Hospital and the Ottawa Hospital Research Institute shaken and vowing to continue her research into the role placental health plays in pregnancy, birth and later health. Gruslin’s death has also touched current and former patients who remember her as an obstetrician who would hold their hands when they needed comfort. Tributes also poured in from researchers around the world.
“To say Andrée was a high valued member of our medical community simply does not do her justice,” said Dr. Jack Kitts, president and CEO of The Ottawa Hospital and Dr. Duncan Stewart, president and CEO of The Ottawa Hospital Research Institute in a memo to staff. “She was a caring physician and scientist who put her humanity at the centre of all she did.”
At the time of her death, she ran a research program into the links between obesity and maternal-newborn health, work for which she won a provincial prize earlier this year.
Colleagues and friends recalled her energy and passion for her work, her infectious enthusiasm—and her love of shoes.
At a celebration of her life in June the stage “was adorned by pairs of Jimmy Choos, Christian Laboutins and Manolo Blahnics,” wrote Mark Walker, The Ottawa Hospital’s chief of obstetrics, in a memo to staff.
“The ceremony was completely arranged by Andrée in her final days. It was not for her, but for us, her parting gift.”
Her colleague and friend Dr. Shannon Bainbridge-Whiteside experienced up close Gruslin’s passion to help mothers and babies by better understanding the workings of the placenta.
“She was a clinician, seeing these women every day. She would come to the lab and say ‘We have to study this because this woman is about to lose her baby at 20 weeks’.”
Bainbridge-Whiteside, assistant professor at the interdisciplinary school of health sciences at the University of Ottawa, jumped at a job in Ottawa when she was offered it so that she could work closely with her mentor. Gruslin even went to bat for Bainbridge-Whiteside when the promise of lab space didn’t materialize and gave her space in her own lab until it did.
Long before the medical world paid it much attention, Gruslin believed the placenta was the key to most risks associated with pregnancy. She spent her life researching placental health as a way of reducing risk from conditions such as pre-eclamp
sia that can result in fetal and maternal death. Pre-eclampsia affects three to seven per cent of all pregnancies.
Just days before she died, Gruslin was on the phone setting up a fund at The Ottawa Hospital Foundation to ensure research into placental health continues in Ottawa.
And Bainbridge-Whiteside said she made her promise that research into the placental health would continue to be a priority in Ottawa. “I am going to make sure this keeps going.”
Among Gruslin’s goals was to design screening tools for fetal and maternal illnesses caused by placental dysfunction, and eventually to come up with treatments or cures.
Bainbridge-Whiteside said the placenta had long been overlooked until researchers like Gruslin began focusing on it as a key to risks associated with pregnancy. “It is starting to get attention now.”
Despite the fact that Gruslin had been battling breast cancer for a decade, her death shocked many colleagues, because she had continued working—usually with a smile on her face and “fully energized”—until weeks before her death.
“I think we all knew it was coming. She was just amazing at not letting anyone know. So none of us really prepared ourselves for this.”
Jeff Turnbull, The Ottawa Hospital’s chief of staff, said Gruslin “was a person who could balance something not many of us can do—excellent clinical care with superb teaching and research.
“She had this curiosity and this excitement about medicine and the science of medicine and research,” he said. “We are all shattered.”
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2014OBJECTIVE 3A: TREATMENT
GYNUITY HEALTH PROJECTS ORAL ANTIHYPERTENSIVE TRIALPrincipal Investigator:Hillary Bracken
OVERVIEW
Pre-eclampsia, and in particular severe pre-eclampsia, represents a significant risk to maternal health. Treatment of elevated blood pressure – one of the primary signs of pre-eclampsia – reduces the risk for maternal complications such as cerebral haemorrhage and cerebral oedema. Regimens for the acute treatment of very high blood pressure (sBP ≥160mmHg and/or dBP ≥110mmHg) that have been subjected to clinical trials have generally used medications administered intravenously (e.g., hydralazine and labetalol).
While these regimens are effective, they present challenges in low-resource settings. They require intravenous access and careful monitoring as they may reduce blood pressure overly rapidly, potentially destabilising maternal haemodynamics at the expense of the fetal condition. A number of oral strategies have been suggested, and a few have been described in clinical practice. However, there is only a single small trial comparing oral regimens alone. Evidence of the relative risks and benefits of different oral regimens will help to develop the data to provide guidance for antihypertensive use in pregnancy, especially where multiple drugs are available.
YEAR THREE PROGRESS
In January 2014, we completed enrolment in the pilot study. The objective of the trial was to examine the feasibility of a randomised trial to determine whether oral regimens of nifedipine, labetalol or methyldopa are effective for acute control of severe hypertension in pregnancy. In the open label pilot study, 30 pregnant women in India with a sustained sBP ≥160mmHg or dBP ≥110mmHg were assigned sequentially to receive oral nifedipine (10mg up to 3 total doses in 6 hours) (n=10), oral labetalol (200mg up to 3 total doses in 6 hours) (n=10), or a single dose of oral methyldopa 1000mg (n=10) until the target blood pressure of 130–150 mmHg systolic and 80–100 mmHg diastolic was achieved. The primary endpoint of the study was
achievement of the targeted blood pressure within 6 hours without an adverse outcome. Secondary outcomes were use of additional antihypertensives, adverse maternal and neonatal effects, and side effect profile.
In the pilot study, most women achieved the target blood pressure within 6 hours without use of additional agents or adverse outcomes (nifedipine: 8/10; labetalol: 9/10; methyldopa: 5/10). Five in the methyldopa arm received additional medication for hypertension; 2 with successful control and 3 unsuccessful. One in the nifedipine arm received additional medication for tachycardia. Most women in the nifedipine arm (9/10) became tachycardic (pulse>105) at one or more monitoring visits. No serious adverse maternal or perinatal side effects occurred.
Based on the results of the pilot, we concluded that the oral regimens of nifedipine, labetalol and methyldopa are potentially effective justifying a randomised trial of all three medications with the current dosing regimens. Findings were used to adjust operational design of the trial. An abstract summarizing the study findings was presented as a poster at the ISSHP World Congress 2014 in New Orleans, USA.
In February 2014, the Indian Council of Medical Research requested that we submit an application to the Drug Controller General of India (DCGI) for the trial. Once the necessary approval is obtained from the DCGI, enrolment in the randomised trial will commence.
YEAR FIVE ANTICIPATED DELIVERABLES
Once the necessary approval is obtained from the DCGI, enrollment in the randomised trial will commence.
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CLIP (COMMUNITY LEVEL INTERVENTIONS FOR PRE-ECLAMPSIA)Co- Principal Investigators:Peter von Dadelszen, Zulfiqar Bhutta
OVERVIEW
The Community Level Interventions for Pre-eclampsia (CLIP) trial is a cluster randomised controlled trial that tests the impact of a package on antenatal care interventions specifically designed to improve community level care for women with a hypertensive disorder of pregnancy. This package includes:
Community engagement to improve community understanding of general pregnancy danger signs and symptoms along with those warning signs specific to the HDP. Community engagement is also designed to increase awareness of the importance of regular antenatal care. Regular monitoring of pregnancies by community health care providers (cHCPs) in the home or at the primary health centre including blood pressure measurement; proteinuria assessment; and symptom assessment. Community level treatment with i.m. magnesium sulphate and oral methyldopa when indicated. Recommendations for referral to a higher level health facilities for all women identified as being hypertensive in the community.
The trial is being undertaken in Nigeria, Mozambique, Pakistan and India. In Nigeria the health workers involved are the Community Health Extension Workers (CHEWS), and for the definitive trial the Health Assistants (HAs); in Mozambique the Agentes Polivalentes Elementares (APEs), in Pakistan the Lady Heath Workers (LHW) and in India the Accredited Social Health Activists (ASHAs) and Auxiliary Nurse Midwives (ANMs). cHCPs in intervention clusters are provided with enhanced training programmes in order to learn all of the new CLIP trial-related tasks while community health care providers in control clusters continue to provide care based on their local standard practice.
The CLIP trial is based on the concept of task-shifting. Task-shifting in CLIP is supported through the use of a mobile phone based decision aid called the PIERS on the Move app which guides the cHCPs through a study visit. This (POM) study visit includes measurement of blood pressure using a semi-automated aneroid device and proteinuria using a dipstick; app-facilitated gestational age calculation; and symptom assessment. At the completion of the visit the POM
app provides the cHCP with recommendations for follow-up treatment or referral as required.
The CLIP trial is completed in three phases. The first phase was a Feasibility study in each country to establish community and health care system capacity to complete the CLIP trial and to determine potential barriers and facilitators to trial success so that these may be addressed prior to the start of the trial. The feasibility study was completed in 2012 in Nigeria, Pakistan and India and is reported in the previous year’s report. Mozambique has completed the feasibility phase this year and results are presented below.
The second phase of the trial are Pilot trials, now underway in Nigeria and completed in Pakistan and India. The primary outcome for these trials is 50% acceptance of referral recommendations by the woman with hypertension. This phase is also being completed to ensure all study tools and processes are functioning properly prior to the start of the Definitive trial. The Definitive trial phase will begin later this year and will continue for two years in all participating countries. The primary outcome for the Definitive trial is a 20% reduction in combined maternal and perinatal mortality or major morbidity.
YEAR FOUR PROGRESS
Significant progress has been made in all countries in the past year as they progress through the trial phases. Mozambique has now finished the qualitative component of their feasibility study as well as their baseline household survey. In the three remaining countries, the Pilot trials are now all past the halfway point and interim analysis has been completed. As of September there have been 16,000 women with pregnancies registered in the three trials. In all Pilot trials there have been challenges faced and overcome. This phase of the study has been very important to the teams, providing great opportunity to learn and refine the trial processes in preparation for the Definitive trial start.
Some of the critical lessons learnt during the Pilot are that the cHCPs in all countries are capable of learning the new tasks assigned and providing the CLIP intervention. This learning requires some time and hands-on training seems to result in greater knowledge retention. In all countries some retraining on use of the POM was required as this was found to be the most complex aspect of the intervention to learn. Despite the challenge of learning the POM, all cHCPs have responded with enthusiasm to the new tools and have reported that use of the POM has made their job easier. The POM allows them to communicate with the pregnant women quickly the dangers/adverse effects of their clinical condition in pregnancy and thereby facilitates more effectively the immediate acceptance of the appropriate medical attention needed by the women.
The Pilot trials have also taught us the importance of community engagement and involvement of stakeholders in the early stages of the trial. In those countries that began community engagement activities either before or at the same time as the health care provider intervention began, acceptance of the referral recommendations was higher from the start.
Finally, the other major lesson learnt is that data management in the CLIP trial is extremely important and complex. The amount of data being generated is significant and building quickly. Careful monitoring of data quality with timely feedback to all trial staff is essential to meeting the trial objectives. The teams in all countries have proven their abilities in this area and have been able to respond to the queries and comments from the central UBC data management team effectively. Although the teams have been keeping up with the volume of work generated by the data collected, it has been a challenging part of the Pilot to date. If we are to maintain data quality throughout the trial the volume of data collected may need to be reduced. Now that the initial rounds of surveillance are complete, we have been able to review data collected and suggest revisions to all data collection forms in order to ensure workload for all staff is manageable and data collected is of high quality.
Updates on trial activity for each country are provided below. In addition, a summary table describing results of the baseline household survey for all countries is provided. This survey was performed to determine cluster level rates of maternal and perinatal outcomes along with birth rates so that sample size estimates could be confirmed.
Expected Actual
CLIP Pilot Trial Enrollment in Nigeria, Pakistan, and India
18000
16000
14000
12000
10000
8000
6000
4000
2000
0
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-12
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2014Table 3: Baseline household survey results for all CLIP participating countries aggregated for the entire study area.
NIGERIA MOZAMBIQUE PAKISTAN INDIA*
Number of WRA 37562 37,568 100,005 9,019
Number of WRA with one or more pregnancy reported (n(%))
8995 (24%)In past 12 months
32,593(86.8%)In lifetime
19,584 (19.6%)In past 12 months
n/a
IN PAST 12 MONTHS:
Number of completed pregnancies
4,606 8,30(22.3%)
19,584 6,293
Number of pregnancies resulting in a live birth (n(%))
4311 (91.9%) 5,226(62.3%)
16,261 (83%) 5,800
Number of pregnancies resulting in a stillbirth (n(%))
1042.4% 286(3.4%)
685 (3.5%) 133 (%)
Number of pregnancies resulting in a miscarriage (n(%))
341 7.2% 176(2.1%)
2,655 (13.6%) 233 (3.6%)
IN PAST 12 MONTHS:
WRA deaths reported 312 (18 maternal) 182 271 5
Children deaths reported up to 1 month of age
91 185 485 122*
Within 1 week 63 n/a 367 90
Between 1 week and 1 month 28 n/a 118 32
* Indian registry is prospective so data presented represent that collected from October 2013 – September 2014 and child deaths report-ed to 6 weeks instead of 28 days.
CLIP FEASIBILITY STUDYCo-Principal Investigators: Rahat Qureshi & Peter von Dadelszen
METHODS
Multiple methods of data collection have been employed to explore enabling and disabling factors for the CLIP trial in Nigeria, Mozambique, Pakistan, and India. Qualitative data have been collected through focus group discussions and in-depth interviews with diverse groups of community members, care providers, and policy makers. In addition, document review and participatory observations have been conducted. Quantitative data have been collected through health facility assessment, self-administered questionnaires and community surveillance.
Focus Group Discussions
Community perspectives have been obtained through focus group discussions by women of reproductive age (represented by pregnant women and mothers with children under five), opinion leaders (represented by religious leaders and elders), and male and female decision makers including family members, particularly mothers-in-law. In addition, a variety of other health care providers have been included in focus group discussion due to their key role in health care service delivery: medical officers, obstetricians, faith-based providers, and traditional birth attendants.
In-Depth Interviews
Key policy makers have been targetted for in-depth interviews, these include: local opinion leaders, administrative heads, and hospital administrators. Health care providers included those in the formal (public and private) health care system as well as traditional birth attendants.
Document Review
A systematic review of community health worker curricula have been conducted in all countries to determine their scope of responsibility. All relevant documents have been assessed in relation to the planned CLIP activities: community engagement, home visits, and domiciliary administration of intramuscular injections and oral medication in pregnancy.
Participatory Observation
Participatory observations have been conducted concurrent with all focus group discussions, one researcher being designated to observe and record field notes. In addition, a structured participatory observation was employed in Nigeria during a full antenatal day in four primary health centres.
Facility Assessment
Facility assessments have been used in the Feasibility Study to map facility locations, costs, available resources and services. Both public and private institutions have been evaluated in this process to gain insight to health care services in the region.
Self-Administered Questionnaires
Self-administered surveys have been used to evaluate current knowledge, skills and readiness of cHCPs before the CLIP cRCT.
Community Surveillance
This surveillance activity focussed on past obstetric and general medical history for women of reproductive age over a 12 month period in Nigeria, Mozambique and Pakistan, as well as household socio-demographic information. In India, these data were collected prospectively over a 5 month period in pregnant women. The primary objective of this data collection was to establish disease rates in the study communities to accurately assess the burden of disease and ultimate effectiveness of the intervention. Secondly, the community surveillance will serve to confirm the epidemiology of disease progression and presentation in target regions. Moreover, it enabled the team to beta-test the surveillance processes prior to the trial.
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Table 4: Distribution of focus group discussions.
LEVEL FOCUS GROUPSSITES
TOTALMozambique Nigeria Pakistan India
Community
Women of reproductive age, and pregnant women
5 16 19 5 45
Male and female decision makers (husbands/partners, fathers-in-law, & mothers-in-law)
10 4 7 6 27
Opinion leaders or community stakeholders
1 4 - 2 7
Health committees 1 - - - 1
Care provider
Community health care providers
5 7 7 4 23
Medical officers, and obstetricians
- 1 - 1 2
Nurses and midwives - 4 - 4 8
Faith-based care providers
- 1 - - 1
Matrons/Traditional birth attendants
5 4 - - 9
Supervisors and trainers
- - - - -
Total 27 41 33 22 124
Table 5: Distribution of in-depth interviews.
LEVEL IN-DEPTH INFORMANTS
SITES
TOTALMozambique Nigeria Pakistan India
Policymakers
Opinion leaders, and community stakeholders
- 4 - - 4
Head of local government and programme directors
- 7 - - 7
Hospital administrators and supervisors of community health workers
3 12 10 - 25
Care providers
Medical doctors, specialists/SOG members, gynaecologists, senior health administrators, and private practitioners
5 11 9 12 37
Traditional birth attendants, and traditional healers
5 5 7 - 17
Community
Local NGO representatives
5 - - - 5
Knowledgeable women / matrons
5 - - - 5
Total 23 39 26 12 100
Table 6: Health facilities audited or surveyed.
FACILITIES AUDITED/VISITEDSITES
TOTALMozambique Nigeria Pakistan India
Public primary/secondary health facilities
53 47 14 17 124
Public tertiary/quarternary health facilities
3 1 1 2 7
Private secondary/tertiary health facilities
16 12 65 100
Laboratories - - 25 - 25
Drug stores/pharmacies - - 81 - 81
Total 56 64 133 84 337
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COMMUNITY HEALTHCARE PROVIDER COUNTRY NUMBER
Lady health workers Pakistan 458
Auxiliary nurse midwives India 8
Staff nurses India 2
Agente Polivalente Elementar (APEs) Mozambique 81
MOZAMBIQUE CLIP FEASIBILITY STUDY
The Feasibility Study in Mozambique was led by PIs Khátia Munguambe and Esperança Sevene. Additional investigators for the study in Mozambique include Clara Menendez, Eusebio Macete, Ariel Nhacolo, Charfudin Sacoor, Helena Boene, Orvalho Joaquim and Abel Nhama.
Picture 12: Members of CLIP team in Mozambique pictured testing the
POM app with the pulse oximeter.
Overview
In Mozambique, the Feasibility Study has been conducted in six districts: Manhica, Magude, Chokwe, Bilene-Macia, Xai-Xai, and Chibuto. The qualitative components were conducted in a sub-sample of three selected districts: Bilene-Macia, Manhica, and Xai-Xai. These areas were selected purposely to capture variety in rural/semi-rural characteristics, population density, access to and distance from main trading centres, and the presence or absence of referral health facilities.
Year Four Progress
The CLIP Feasibility Study in Mozambique has completed all qualitative data collection, entry and analysis. Data collection, cleaning and analysis were conducted by the local team in close communication with the co-ordinating centre at UBC. Analysis was conducted with NVivo 10 software for qualitative data. This approach allowed thematic analysis guided by the Feasibility objectives, discussion guides and emerging themes. The findings of the Feasibility Study highlight the key community factors, resources and infrastructure capacities which may influence the CLIP cRCT in Mozambique.
Results
Objective 1: Determine stakeholder support
APEs supervisors at the district level did not identify major concerns regarding the involvement of APEs in the management and referral of pre-eclampsia at the community level. However, they did raise concerns regarding the current training programme, and its ability to appropriate prepare APEs to provide intramuscular injections. There was moderate support for the administration of an oral antihypertensive in the appropriate women. Community engagement activities were strongly supported by all stakeholders. Overall there was strong support from stakeholders though some had reservations in the provision of injections by APEs.
Objective 2: Determine health care system organisation and infrastructure capacity
Antenatal visits consist of a physical assessment which includes measurements of weight, blood pressure, arm circumference and fetal growth. In addition, there is screening of the most prevalent infections in pregnancy: HIV, malaria, syphilis and urinary tract infections. During antenatal visits women receive intermittent preventive treatment for malaria, tetanus toxoid vaccine, supplementation, anthelmintics, insecticide treated nets, and prevention of mother-to-child HIV transmission when needed. Pregnant women generally attend at least 1 antenatal visit during pregnancy but this varies from 1 to 5. The first visit is most commonly after 20 weeks of gestation. Some health facilities lack access to pregnancy testing; as a result women
are encouraged to seek care when pregnancy signs become obvious. This may account for some delays in the identification of pregnancies. All antenatal care services are free of charge.
When a pregnant woman is identified with warning signs at a primary health facility she is referred to the second level of care. Referrals are usually completed by ambulance; 96% of health facilities reported to have an ambulance or other vehicle available.
It was found that ten facilities (22%) do not have electricity routinely during working hours. Digital blood pressure machines were most often available in primary level facilities (65%), while manual sphygmomanometers were available in other facilities (35% at the primary level). All facilities reported at least one type of blood pressure device (digital or manual). Magnesium sulphate is available in most of the health facilities at primary level (83%) and all facilities at secondary, tertiary and quaternary levels, although stock outs have been reported.
Objective 3: Determine cultural and community beliefs / practices / influences / attitudes
A wide range of pregnancy complications were mentioned by the community, these include: swollen feet (usually associated to lack of water and blood), weakness, sickness or pain in the womb, haemorrhage, delayed or complicated labour and xithetho (a condition where the uterus “reject the fetus”). Traditional healers, matrons and elders who are the main alternative health providers at the community level, mentioned high blood pressure and illness of the heart as important pregnancy complications, which according to them, were not very common. The main causes of pregnancy complications were social and gender-based, such as discrimination or violence, suffering, and heavy domestic work load. Haemorrhage was thought to be caused by refusal by women to take bitter remedies during pregnancy which include both drugs prescribed by the health facility and alternative health providers. Another important cause of pregnancy complications is pregnant women’s intimate involvement with different partners because it is believed that the blood of the pregnancy “owner” cannot be mixed with another man’s blood.
The terms “pre-eclampsia and eclampsia” were not known by the community members. Pre-eclampsia is known as high blood pressure (tensão alta), or simply pressure (tensão), illness of the heart (mavabji ya mbilu or mavabji ya timpfalu) and fainting disease. Eclampsia, characterised by convulsions, is referred to as illness of the moon (mavabji ya nweti), snake illness (nhocane), illness of the heart, falling disease, children’s illness (mavabji ya vatsonguana), the big illness (mavabji ya makulo), frightening illness (mavabji ya kudzuka), and epilepsy. The perceived causes of pre-eclampsia mentioned were: mistreatment by the in-laws, excessive thinking and worrying, anger, marital problems, eating food with too much salt and sadness. The main outcomes of pre-eclampsia were thought to be abortion, premature delivery and maternal death. Loss of speech and
headache were mentioned as immediate consequences of eclampsia. It was also mentioned that women’s limbs become paralysed as a direct consequence of the fall. According to the community members, for treatment of pre-eclampsia and eclampsia, the health facility is recommended. Health care providers mentioned the use of antihypertensives and MgSO
4 for treatment. Traditional treatments for these illnesses do not seem to be common or believed to be effective.
Women encounter several challenges in seeking health care services; these include unavailability of transport, high cost of transport, and lack of family support. There are limited transport services available particularly in areas off the main roads. Husbands and other relatives often have important roles in decision making which may prevent women from seeking care when and where desired.
Objective 4: Determine the potential for scale-up and task-shifting for cHCPs
APEs are an important element of the primary health care system in Mozambique; their training programme was updated in 2010. The duration of the training is 16 to 18 weeks and requires the APEs to remain in the training centre for the duration. APEs are provided a kit to best serve their community and manage common health concerns. Their time is divided between preventative (80%) and curative activities (20%).
There are two major barriers for scale-up and task-shifting: their academic qualification and the conditions for remuneration. Due to the low number of APEs available it is not possible to cover some communities and results in a need to travel long distances. APEs are selected by their communities, with preference given to women; nevertheless 80% of the current APEs are men. The presence of different partners, mostly NGOs with interventions at community level, attracts the APEs to these organisations; therefore retention in the system is a challenge.
Objective 5: Assess cHCP competency and resource / informational capacity for provider training and develop appropriate training package
The training includes 9 weeks of theory-based learning, 8 weeks of practice, and 1 week for evaluation. During this period the APEs are exposed to 4 modules including (a) the role of APEs and community engagement strategy; (b) promotion of health and prevention of diseases at the community level; (c) emergency care and management of the most common diseases at community and (d) general review of the topics and evaluation. None of the modules include education specific to pre-eclampsia and eclampsia. The APEs training programme allocates 2 weeks for theory and practice per condition. Using this reference we think that 2 weeks will be enough for the addition of the CLIP training.
Only 10% of the interviewed APEs feel that they have the ability to measure blood pressure, yet the majority of APEs
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Ninety-two percent of APEs reported that they were able to recognise symptoms of pregnancy complications, yet only 40% and 70%, respectively, were capable of recognising the signs of high blood pressure and convulsions.
Objective 6: Pilot test the education and intervention package for acceptability and barriers identification
Training manuals have been developed for use in the CLIP trial. APEs training is taking place in November 2014.
Objective 7: Identify / develop data collection tools for community and facility surveillance assessments in both the intervention and control clusters, develop a database, and obtain pre-intervention cluster level data
Facility assessments were conducted across 56 facilities to provide insight to the availability and use of pre-eclampsia and eclampsia treatments. Most health facilities surveyed (82%, 46/56) offer primary level health care. The facility records appear to be incomplete with respect to pregnancy outcomes. The numbers of maternal deaths and stillbirth are lower than expected and suggest under-reporting.
The baseline surveillance activities began in March 2014.
Objective 8: Identify potential barriers to project success and commitments to remedy identified barriers
At the provincial level, there were some doubts about APEs participating in the CLIP programme. The major health system weakness is an effective link between the health facility and APEs in the context of supervision. At the central level, the MOH showed concern about health facilities lack of reliable equipment to measure blood pressure and requested that the CLIP trial to equip such health facilities with blood pressure devices.
Objective 9: Conduct a cost identification analysis to conduct an adequately-powered Definitive CLIP cRCT
Cost identification for the definitive CLIP trial was completed in August 2014. Further costing of required elements of the CLIP package has been completed by the CISM team. The intervention package will require 60 APEs assigned to 6 clusters. The assumption for the resources required is that each APEs in the intervention area will cover about 320 pregnant women, over a period of 24 months.
Year Five Deliverables
The remediation of barriers raised through the Feasibility study is on-going. Publications are now being drafted to reflect the findings of the Feasibility Study. The Definitive trial begins in
November 2014 The data collection for the baseline surveillance is ongoing and will be complete September 2014.
NIGERIA CLIP PILOT TRIAL
In the past year the Nigerian team has successfully completed their baseline household survey allowing sample size estimates to be confirmed. The estimated maternal mortality ratio (MMR) for the cluster areas based on this survey was found to be 418/ 100,000 live births. The MMR is slightly lower than that reported by the WHO and World Bank for Nigeria in 2013 (reported as 560/100,000 live births). The neonatal mortality ratio is 21/1000 live births, which is also somewhat lower than the countries reported figure of 39/1000 live births. This came as no surprise for the research team who were expecting Ogun State to have lower rates of mortality than the country, on average, as the health care infrastructure is considered to be more established in this region. The team is actively investigating these results to determine the reason for the discrepancy. One thing to note in this analysis is that our survey is based on a complete population survey, rather than estimated using partial facility and community based data, as is the case with the World Bank estimates. It is possible that the household survey results are a more accurate reflection of mortality rates in Nigeria.
Picture 13: Surveillance officer (right) visiting a household in Nigeria, conducting data collection.
The Nigerian Pilot trial officially began in March 2014 due to an ethics approval delay after successful training of all health workers in December 2013. As of 30 September 2014, there have been 7300 women enrolled in the study and 2068 women have completed one or more CLIP study visit with a CHEW in an intervention cluster. The total number of CLIP visits completed
is 4597. Based on the data collected up to September of this year, the rate of HDP in intervention clusters is 4.2%. There have been 105 study visits resulting in a recommendation to seek higher level care; either urgently or within 24 hours. The most frequent indication for urgent referral is severe hypertension, accounting for 66% of referral recommendations.
The first challenge the team encountered was in accessing pregnant women for both pregnancy registration and for study visits. Initial review of the trial data showed that coverage of the intervention (measured as the proportion of women enrolled in the study in intervention clusters who have received at least one study visit) was only 53%. The team quickly responded to this by determining that many women were going to private clinics for antenatal care or to secondary facilities. To increase coverage in the study they have gained permission to work with the community health care providers in these additional clinics and facilities. Training of these additional staff, called health assistants, participate in the trial is now complete and we expect coverage to improve in the second half of the Pilot trial.
Other notable activities completed in Nigeria this year include a stakeholders’ meeting at the Abeokuta Ogun State Headquarters on December 4th 2013 and continuous professional development events for both medical officers in referral facilities and all staff in intervention cluster primary health centres (PHCs) during February and March 2014.
The team has completed of 23 cycles of community engagement events in the two Pilot intervention clusters. These events have reached a total of 1519 community members spread across the following stakeholders groups: women group; TBAs; community leaders; men’s groups; community development associations; women of reproductive age; association transport workers; decision-makers; and faith-based maternity care providers. Also included in the community engagement groups are the community health workers (CHEWs, Health Assistants; Health Attendants and Community Midwives; Associations of Landlords, pregnant women and husbands). A final important achievement by the Nigeria team relating to community engagement was the successful launch of a revolving loan programme for immediate transport in the intervention cluster areas. This programme began as of March 2014.
Community response to the pilot has been positive overall. This is reflected in the high level of acceptance of CHEW/HA recommendations for community treatment when severe cases of pre-eclampsia is encountered. A notable case is described below.
Picture 14: A pregnant woman, enrolled in the CLIP trial being attended to by a CHEW using the POM app. She was discovered to have
pre-eclampsia.
A case of hypertensive disease of pregnancy in a woman enrolled in the trial was reported at term in a faith-based maternity centre, very near her abode. At the private health clinic, the faith-based attendant, who had participated in CLIP community engagement programme suspected pre-eclampsia called for help from the CLIP team.
The patient was transferred to a nearby PHC by the CLIP team. There she had her blood pressure measured and completed a study visit using the POM. Based on this assessment she was recommended for referral to secondary level of care within 4 hours after receiving methyldopa 750mg and magnesium sulphate 10g.
She failed to report at the secondary level care because her husband was not around to give her permission to go or provide funds. When the CLIP team could not locate her at the secondary health care hospital, the team went after her and met her at home. She was convinced of the importance of getting care in the hospital. Therefore, her neighbour followed her to the hospital.
At this time which was six hours after the first referral, the proteinuria had became more worse and the blood pressure had risen from 160/105 to 170/110. She had a repeat of magnesium sulphate and methyldopa in the hospital and was delivered by Caesarean section of a twin pregnancy. She recovered satisfactorily and both mother and the twins are alive and well. The CLIP team recognised here the impact of community engagement that had been conducted earlier for a group of community leaders in that locality.
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Picture 15 and 16: Twin delivery from women who suffered
pre-eclampsia in Nigeria.
PAKISTAN CLIP PILOT STUDY
Picture 17: A lady health worker (pictured left) conducting a postpartum visit with a woman(pictured middle with her baby) enrolled in the CLIP
Study.
The Pakistan team got off to a great start in Year 4, quickly completing their baseline household survey. This survey was not only useful in that it allowed us to estimate rates of maternal and neonatal mortality in the CLIP cluster areas, but it highlighted a few issues with the surveillance forms that we were able to address prior to the Pilot trial. One in particular relates to the absence of a word for pre-eclampsia or even hypertension in the local Sindhi language. On the baseline survey it was noted that more than 60% of the women reported having hypertension in a previous pregnancy, oddly this was almost the same rate as that reporting severe headaches. It was clear from review of this data and discussion with field staff that women understood the two concepts as the same medical issue. Based on this, the wording of the question relating to hypertension was changed for the Pilot trial and data collection has improved. The baseline survey generated estimates of MMR of 233/100,000 live births and NMR of 29/1000 live births in Sindh province. These compare to the rates reported by the World Bank of 170/100,000 and 42/ 1000 live births, respectively.
The Pilot trial began in Pakistan in late February. As of 30 September 2014 there have been 4433 women enrolled in the Pilot study and 1381 women with one or more CLIP visit completed in the intervention clusters. This represents a total of 4056 CLIP study visits completed! The rate of HDP identified in Pilot clusters to date is 2.3% and number of referrals recommended (either urgent or non-urgent) is 91. The primary indication for referral is severe hypertension. These numbers are within the expected rates demonstrating excellent coverage
of the intervention is being achieved in the Pilot trial intervention cluster areas.
Initially the research staff were accompanying the Lady Health Workers for all CLIP visits and entering data into the POM. This will be changing in the Definitive trial as a core concept that the CLIP trial is testing is the ability to task-shift using mobile technology clinical aspects of monitoring and treatment of women with HDP to cHCPs. This cannot be accomplished unless the health care providers are in charge of administering the whole intervention themselves. We thank the Pakistan team for their support of the health workers as this transition happens. Another key aspect of the change to health worker led visits will be introduction of the Phone Oximeter as part of the CLIP monitoring visits in Pakistan. All women will have their blood oxygen levels measured during the first CLIP study visit and at any subsequent visit where hypertension is found.
Undoubtedly, the biggest challenge faced in Pakistan to date has been a low level of acceptance of treatment with MgSO
4 by women in the community when it is indicated. There are many possible reasons for this including close proximity to health facilities in one cluster but the primary reason that has been provided by the field staff is lack of permission for transport or further care by the woman’s husband, or lack of funds available to seek care. The Pakistan team has been working hard to address these barriers through the community engagement events and by setting up a voucher system to assist with transport costs while community funds are being developed. The final analysis of the Pilot data will show us if we are moving in the right direction to address this concern.
To give a greater context to the information provided here the Pakistan team would like to share a story from the field of the CLIP intervention in action.
A 30 year old woman, in her 12th pregnancy, having delivered live children seven times, was registered in the CLIP trial at 34 weeks of gestation. She has 7 healthy children which include 4 boys and 3 girls. In addition, she had a history of 4 second trimester miscarriages over the past 4 years, the last one of which was associated with high blood pressure.
On her initial two pregnancy follow up visits by the CLIP team, her BP was recorded to be 145/89 and 155/95 respectively, with no signs and symptoms nor proteinuria. The POM recommendation for each of these visits was non-urgent referral which was refused by the woman due to lack of money. However, on the third and last pregnancy follow-up visit, her BP was recorded to be 165/96, 3+ proteinuria on dipstick along with headache and visual disturbances. According to POM recommendations, 750mg methyldopa and MgSO
4 were administered and urgent referral was given and accepted by the woman. She chose to attend a nearby private facility after this
recommendation for referral was made at which she was given a multivitamin and then sent home.
She delivered a healthy baby boy at home with the help of her mother in law who also happens to be a traditional birth attendant. After delivery, her BP was recorded to be 164/101, 1+ proteinuria along with headache and visual disturbance. Based on POM recommendations, 750mg methyldopa and MgSO4 were administered and an urgent referral recommendation was made, which was declined by the women due to lack of money.
On her subsequent three postpartum visits, her BP was still raised along with 1+ proteinuria on each visit. She declined MgSO4 treatment that was recommended by POM for each visit but accepted 750 methyldopa and referral to the health facility.
On our recent visit to the family, the infant is now 3 months old and both the mother and baby are in good health. The mother also appreciated the CLIP team’s effort in managing her well during the previous visits.
INDIA
Picture 18: Dr Geetanjali Katageri, member of CLIP India Bagalkot team
discusses the POM app with ASHA workers in Bagalkot, India.
The India team worked incredibly hard over the past year to meet the milestones set at the initiation of the CLIP trial and started their Pilot trial in February 2014. Prior to initiating the trial, the team established a prospective maternal and child health registry in the CLIP trial cluster areas. This has been a
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allow us to collect high quality, community level data on the entire study population without reducing the risk of recall bias that occurs through the quarterly household surveys.
Setting up this registry has not been without challenges. The first was a systematic under-reporting of adverse health outcomes for the women and fetuses/newborns in the first few months of work. This was recognised by the team based on a comparison of the CLIP cohort data with registry data collected in other parts of Karnataka State. The team was able to correct this problem through successful community engagement meetings to gain the support and trust of the community, and through some re-training of the registry staff. In addition, they completed a household survey to determine where events may have been missed and have been able to correct some of the data to better reflect community level rates of maternal and perinatal mortality. Based on data from the first six months of the registry, these rates are 86/100,000 live births and 21/1000 livebirths for MMR and NMR, respectively. These numbers are both lower than that reported for India by the World Bank, which were 190/100,000 and 31/1000 live births, respectively.
Since the start of the registry and up until September 2014, 9,019 women have been enrolled in the CLIP study. 849 women have completed one or more CLIP study visits in an intervention cluster and a total of 2921 study visits completed as of 30 September, 2014. The rate of HDP identified in the intervention clusters by the health workers is 1.6%. This rate is lower than expected which has led to the first change of the CLIP trial to date. Common practice around childbirth in this area of India is for the pregnant women to leave her marriage home to live with her mother in-law at approximately 7 months of pregnancy until about 3 months postpartum. As the majority of HDP occur at or near term, it is likely that this outmigration in the late preterm period is reducing the rate of HDP identified in the trial. The team has responded to this issue in several ways: (1) working with the community they have ensured that information is collected during pregnancy registration that will allow the registry staff to follow-up with these women and collect the important pregnancy outcomes, even if they move away; (2) during community engagement a big focus in the messaging has been to encourage women to self-seek care if they are experiencing any signs or symptoms of the HDP, even after they leave a study area; and (3) we have added a button to the POM app to allow the health care provider to indicate when the women does move away. By measuring this practice in the community we will have a better understanding of how it may affect coverage of the intervention and trial outcomes.
Overall the Pilot trial has run in India with great success. There have been 42 women recommended to seek higher-level care, either urgently or within 24 hours. As in Nigeria and Pakistan, the primary indication for referral has been severe hypertension. Acceptance of the treatment and referral advice by health care providers has been nearly 100% in the Pilot trial. We believe this reflects the fantastic job the health care providers and study staff are doing with community engagement, as it appears the
community has fully accepted the new roles of the ASHA and ANM.
In regards to community engagement activities, the India team has now completed one round of community meetings and mothers’ meetings in each of the intervention clusters, visiting all PHCs and sub-centres with great involvement of the community and a very positive response. These events have included women of reproductive age, their husbands and family members, community leaders and health care workers from the area. Highlighting the positive response seen from the community, the India team has the following story from the field to share with us:
One woman who had high blood pressure (sBP >160 mm Hg) was brought by the ANM to the primary health centre so that the ANM could administer her MgSO4 and methyldopa. The woman refused to accept the CLIP treatment; she believed that she did not need treatment as she only had fifteen more days until her estimated delivery date and further, her husband did not allow her to accept the treatment. The CLIP study team in India spoke to members of the family and educated them about the dangers of hypertensive disorders of pregnancy. One of the family members succeeded in convincing the woman to visit a referral facility. Following the treatment, the woman delivered the baby. She expressed gratitude to the CLIP India Team members that she had a healthy baby and averted any dangers that her high blood pressure have caused.
Picture 19: CLIP India PI, Mrutunjaya Bellad (left) visiting a woman who had developed pre-eclampsia but had a successful outcome following acceptance of the CLIP intervention in Marakumbi, India in April 2014.
STRIDER (SILDENAFIL THERAPY IN DISMAL PROGNOSIS EARLY-ONSET INTRAUTERINE GROWTH RESTRICTION)Principal Investigator: Peter von Dadelszen
Funding: Canadian Institutes of Health Research
Severe, early-onset placental intrauterine growth restriction (EO IUGR) is associated with a high risk of perinatal morbidity and mortality. In association with reduced circulating placental growth factor (PlGF) severe EO IUGR results from abnormal placentation with inadequate remodelling of the maternal uteroplacental arteries. There is no known treatment for placental IUGR. Management involves intensive fetal surveillance with delivery with evidence of serious fetal compromise. However, remote from term, delivery is associated with significant perinatal mortality and morbidity.
The overarching aim of the STRIDER (Sildenafil Therapy In Dismal Prognosis Early-Onset Intrauterine Growth Restriction) Canada trial is to determine whether maternal treatment with oral sildenafil citrate improves perinatal outcomes in pregnancies complicated by severe early-onset IUGR without increasing risks to the mother.
STRIDER Canada is one of a consortium of STRIDER randomised controlled trials (RCTs) each of which will be designed to determine whether or not maternal treatment with sildenafil citrate improves markers of perinatal wellbeing.
The UBC group is co-ordinating an international consortium of independently funded STRIDER trials with an a priori planned individual participant data (IPD) meta-analysis at the conclusion of these trials. Currently, these trials are funded in New Zealand and Australia (4 recruits), UK, Ireland, the Netherlands and Canada. Each national trial will be performed using a shared protocol. The primary outcome is post-randomisation abdominal circumference (by ultrasound) growth velocity, prolongation of pregnancy for one week as a surrogate for long-term morbidity, intact perinatal survival until term age and birth weight for Australasia, UK/Ireland, the Netherlands and Canada respectively. After the trials have been completed, then the IPD meta-analysis will have sufficient power for a hard perinatal survival outcome.
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THE GLOBAL PREGNANCY COLABORATORYPrincipal Investigator:Jim Roberts
OVERVIEW
After four years, the original concept guiding the formation of the Global Pregnancy CoLaboratory (CoLab) endures. The overall mission of CoLab has been to improve the health of women and their infants by fostering collaborative research and sharing of biological materials and data. However, the approach has been expanded during the last three years as we worked to harmonise research to further facilitate collaboration. This effort led to the publication of position papers describing optimal approaches to placental research, what can be accomplished with samples collected under different conditions, and the identification of data fields necessary for research to study pre-eclampsia. This was accompanied by recommendations for when and what types of biological material should be collected. We are now using this information to guide production of a standardised database to be used for studies of pre-eclampsia worldwide. In keeping with our participation in the PRE-EMPT initiative our initial efforts are directed at improving care for pre-eclampsia with increasing focus on research relevant to low and middle income countries where the needs are extensive and often
critical. Our long-term goal is to extend the harmonisation efforts to other adverse pregnancy outcomes as well.
YEAR FOUR PROGRESS
We continue to support several projects for investigators both within and outside of CoLab. Please see the list below. A few projects deserve special attention. Our study of angiogenic factors includes data generated in studies from around the world on over 14,000 women. Innovative strategies were used to combine these data, which were acquired with several different “platforms”. A description of this successful effort is now under consideration for publication. The first definitive paper to test hypotheses on the implications of the concentrations of the angiogenic factor, PlGF, is in progress. We anticipate that these data will be a rich source to increase understanding of the relevance of angiogenic and anti-antigenic factors to the genesis of adverse pregnancy outcomes.
CURRENT COLAB PROJECTS INVESTIGATORS
Variation in endoglin pathway genes associated with pre-eclampsia
PI: Mandy Bell SchmellaSponsor: Carl Hubel
Understanding, diagnosing and predicting pregnancy outcome in women with chronic hypertension
PI: Lucy Chappell CoLab CoPIs: Lucilla Poston and Hannele Laivuori
Biomarker assay development for translation of discovery-based placental mRNA candidates to serum protein concentrations in early pregnancy to predict pre-eclampsia
PI: Sandra FoundsSponsor: Jim Roberts
Inflammatory profiling of pre-eclampsia, highlighting fetal gender, parity, BMI and IUGR: a case control study
Maya Jalmby Sponsor: Stefan Hansson
CURRENT COLAB PROJECTS INVESTIGATORS
Maternal circulating angiogenic factors and subtypes of pre-eclampsia
PI: Annetine StaffCoLab Investigators: Chris Redman, Peter von Dadelszen, Roberta Ness, Cuilin Zhang with Samantha Benton, Orlaith Burke and Pawel Szafranski
Sex specific differences in the placental syndrome and markers of placentation
Sarah Schalekamp-Timmermans. Eric Steegers
Urinary tract infection and risk of pre-eclampsia CoLab co-investigators: Tom McElrath and Jenny Myers
Regulatory and administrative institutional obstacles to collaborative research and sharing of biological data and samples. (Submitted manuscript for publication) (Project created during 2013 CoLab Oxford Conference)
Lucilla Poston and Roberta Ness
Development of database to be made available to international research community for harmonisation of PE research.(Project created during 2013 CoLab Oxford Conference)
Chris Redman, Les Myatt, Jenny Myers, Lucilla Poston, and Peter von Dadelszen in collaboration with MedSciNet Project Manager/Software Developer, Laima Juodvirsiene and colleagues
Reverse phenotype cluster analysis of TCA.(Project created during 2013 CoLab Oxford Conference)
Jenny Myers, Les Myatt, Lucilla Poston, Chris Redman, Annetine Staff
External validation and recalibration of the fullPIERS model (PIERS—Pre-eclampsia integrated Estimated RiSk.)
PI: Peter von DadelszenTrainee: Ugochinyere Vivian UkahCoLab Investigators: Christropher Redman, Hannele Laivoire, Alere
Angiogenic factors in the identification of intrauterine growth restriction
PI: Peter von DadelszenTrainee: Samantha Benton
Lactation, Preeclampsia, and maternal risk of CVD Bimla SchwartzSponsor: Jim Roberts
The role of placental microparticles, Toll-like receptors and inflammation in PE
Brandie DePaoli TaylorSponsor: Jim Roberts
At our annual CoLab Conference we heard preliminary results on the relationship of fetal sex to both maternal and fetal outcomes in pre-eclampsia. These data were originally collected at one centre but now will be extended to centres throughout CoLab. Another interesting and potentially quite important study has examined patterns of inflammation as determined by the assessment of more than 100 inflammatory factors. This study revealed clustering of pre-eclampsia cases, which would not have been predicted from the subtypes usually considered. This study is being extended into CoLab centres, which will provide sufficient data to determine the phenotype of women with pre-eclampsia in the resulting clusters of inflammatory markers. We have the completed the Standard Operating Procedures for the collection, storage, and eventual disposition of urine samples being collected in our first LMIC biorepository. This is being carried out in association with Objective 1 of the PRE-EMPT, the CAP Trial. The urine samples will be used in the CAP Trial to measure the calcium/creatinine ratio to determine
both the impact of calcium intake at the initiation of the study and compliance during the study. The residual urine will be stored and used for future studies. Possible studies are now under consideration.
In addition, we initiated a project this year to improve harmonisation and collaboration of pre-eclampsia studies through the development of a standardised online database. This would be made available to investigators worldwide including low and middle income countries (LMICs). Towards this end we have enlisted the assistance of the MedSciNet Company in the development such a database. This will be based upon the data fields recommended in our published paper aimed at harmonising pre-eclampsia research and will be available at no-cost to LMIC or beginning investigators and at a nominal fee to others. Currently, we are polling investigators worldwide for their input.
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2014At the 2013 CoLab Oxford Conference we discussed the
difficulties in performing collaborative research brought about by administrative obstacles (likely unintended). We elected to prepare an article/editorial to make this evident to the public at large. We have accumulated information upon which to base this presentation.
Publications
We had three publications in the last year including two position papers and the strategy of the angiogenic study.
Grant Applications
Our most notable announcement is that Jim Roberts and the Magee Women’s Research Institute received additional funds from the Gates Foundation to support the Global Pregnancy CoLaboratory for an additional three years, co-terminating with the remainder of the current funding envelope for the PRE-EMPT initiative. This is a major renewal of the Foundation’s investment in the CoLab, and should see it through to self-sustainability from peer-reviewed, agency, donor, and industry sources.
We applied for funding for the CoLab European centres from the European Union. This grant, which was submitted to the COST programme, was unsuccessful but information obtained from the review will facilitate a future application. In a similar vein we applied for funding in association with the Indian group, MAMTA, for collaborative funding from the European Union. We are awaiting official decision on this application. We have continued to work with Merck for Mothers for funding of a combined implementation trial and biorepository establishment. We are also exploring the possibility of developing with their support and in conjunction with Alere, a point-of-care assay for the angiogenic factor, PlGF.
Public Relations
In the last year CoLab has received a good deal of positive attention because of our publications. In addition, we made presentations at the International Federation of Placental Associations (IFPA), an even greater presence at the International Society for the Study of Hypertension in Pregnancy (ISSHP) and several other smaller meetings. Through these efforts we hope to extend the usefulness of CoLab by making its availability and resources evident to investigators worldwide.
2014 CoLab Conference
The group met at Oriel College in Oxford during September 2014. The purpose of the meeting was as always to review progress and establish benchmarks for the upcoming year. This year we made as our major goal an attempt to explore the use of “Big Science” to answer the important questions about
pre-eclampsia. Then, we asked whether CoLab had sufficient and appropriate data and biological materials to perform studies to successfully address these questions. If the answer was “no” then we attempted to identify what data and which biological materials would be necessary to accomplish this goal. We invited several guest speakers with expertise in informatics, or the use of “Big Science” to address these questions. As a result of the presentations and interactive discussions we developed several deliverables for 2015 and some longer-range goals. The deliverables are discussed below. One long-range goal is to begin to explore the formation of a “collaboration of collaborations” to bring together several groups that have established collaborations similar to CoLab but at a smaller scale. In addition, we will begin to consider how to address the relationship of pre-eclampsia, preterm birth, intrauterine growth restriction and perhaps even normal pregnancy to later life cardiovascular disease. It was evident in our discussions that many of the questions to improve the management of pre-eclampsia require information and biological materials which were not only not available in CoLab but did not seem to be available anywhere in the world. Thus, another long-range goal is to work with other groups worldwide to begin to assemble appropriate prospective data and biological material collections.
YEAR FIVE ANTICIPATED DELIVERABLES
We will complete the database by the end of the 2015 calendar year. We plan that the manuscript on administrative/institutional impediments to collaborative research will be prepared and published in the coming year. In our attempt to ensure the sustainability of CoLab we have begun conversations with industry to determine if they might use our resources on a fee-for-service basis. In the next year we will explore interest in this approach with member cohorts and establish CoLab strict policies and procedures for such associations. We will prepare a report based upon the findings from the 2014 CoLab Conference of what is necessary for future biobanks and databanks to provide materials to answer the important questions in pre-eclampsia using “Big Science”. We anticipate that our first publication on conclusions based upon the data collected in our angiogenic factor meta-analysis. We will complete the position paper on genetic research. We will seek funding to enable us to set up a biorepository in conjunction with one of the PRE-EMPT centres in India, the CLIP trial. We will continue our efforts to utilize our “Big Science” resources to address the heterogeneity of pre-eclampsia. Our long-term goals continue to extend our efforts beyond pre-eclampsia to the study of other adverse pregnancy outcomes, specifically growth restriction and stillbirths, and to increase our involvement in LMICs.
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KNOWLEDGE TRANSLATIONPrinciple Investigator:Matthews Mathai
OVERVIEW
The purpose of this objective is the development, dissemination, and implementation of evidence based and culturally appropriate knowledge translation tools for both well- and low resourced settings. This is vital in effecting a reduction in the burden of life-ending, life-threatening, and life-altering maternal complications of pre-eclampsia/eclampsia. The evidence-based knowledge translation tools can be used at the level of the communities, the primary health centres (PHC), and the hospitals to improve evidence informed clinical decision –making and patient self-identification of pre-eclampsia symptoms. Furthermore, the document can also be used to inform policy making and implementation of best practices at national and sub-national levels through various channels including ministries of health, professional associations, educational institutions and civil society organisations.
YEAR FOUR PROGRESS
Objective 5 of the PRE-EMPT project focusses on the development of the WHO guideline for pre-eclampsia and eclampsia. This part of the objective was achieved early in the project with the convening of the WHO Guideline Development Group in 2011 followed by the publication of the WHO Recommendations on the Prevention and Treatment of Pre-eclampsia and Eclampsia.
Members of the KT working group continue to be involved through various roles in promoting the implementation of these evidence based recommendations through various channels. Examples include:
• presentations and discussions in fora of health professionals
• working with ministries of health to include these recommendations in national guidelines and training tools
• ensuring quality medicines and competent human resources are available to provide care for women with pre-eclampsia and eclampsia.
In addition, many members of the group are involved with improving accountability in maternal and perinatal health through monitoring of availability of medicines and adherence to best practices during maternal death and near miss reviews. Also some members of the group work with international partners to ensure that magnesium sulphate is one of the life saving commodities in maternal health is available universally.
WHO and The Partnership for Maternal, Newborn and Child Health held a consultation in December 2013 to identify core indicators for quality of care in health facilities. The use of magnesium sulphate in severe pre-eclampsia and eclampsia has been considered as one of six core indicators of quality of maternal health care in facilities.
A research priority setting exercise in maternal and perinatal health using the CHNRI methodology was conducted in 2013. The results were published in 2014. Although, hypertensive disorders of pregnancy were not represented in the top-20 list, it comprised 14% of the research questions in the upper quartile.
YEAR FIVE ANTICIPATED DELIVERABLES
We had achieved most of the objectives in Year 1. Should the results of on-going projects or significantly new evidence on prevention and management of pre-eclampsia become available over the next few months, we will consider a guideline update (subject to availability of additional resources). Until then, the group will continue to transfer current knowledge to improvement in practices for the care of women at risk or who have pre-eclampsia/eclampsia. Members will work with partners to promote best practices for pre-eclampsia and eclampsia prevention and management through advocacy, setting norms and standards, updating national guidelines
and training tools, monitoring and ensuring the available of priority lifesaving medicines, and promoting and monitoring the use of checklists, maternal and perinatal mortality and morbidity reviews and other methods for quality assessment and improvement. Further work on updating guidelines will be planned after work in the other objectives are completed and results published.
THE PREECLAMPSIA FOUNDATIONExecutive Director: Eleni Tsigas
OVERVIEW
Established in 2000, the Preeclampsia Foundation works to reduce maternal and infant illness and death due to pre-eclampsia, HELLP syndrome and other hypertensive disorders of pregnancy through a diverse array of resources and advocacy efforts. The Foundation comprises an empowered community of patients, their relatives and medical experts and is active in raising public awareness, funding research, and providing support and education to the patients as well as healthcare providers, and improving healthcare practices. The Foundation not only provides these resources to help mothers and families to understand and cope with serious complications (and/or losses) but also advocates on behalf of the thousands of individuals whose lives have or will be affected by pre-eclampsia.
In its collaboration with the University of British Columbia, Vancouver, over more than ten years, the Preeclampsia Foundation has enhanced its ability to reach out to the affected women and families in the LMICs as well as to continue to catalyse pre-eclampsia focused research by the LMIC-based clinicians and scientists.
The Executive Director of the Foundation, Eleni Tsigas, has lead the foundation to its current position as a sustainable, mission-driven, results-oriented organisation and serves as a member of the PRE-EMPT Technical Advisory Group and the KT working group.
YEAR FOUR PROGRESS
For several years, The Preeclampsia Foundation has mentored Marshall Ukpoma in Nigeria, a man who lost his wife to pre-eclampsia and has been compelled to advance education and awareness in that country. In the past year, we have connected him with other volunteers in Nigeria who want to work as patient advocates. They have conducted several radio interviews, awareness talks, and launched a website with the assistance of the Foundation http://www.preeclampsiang.com/. They are currently seeking registration as an NGO in that country.
The Preeclampsia Foundation’s “Partners for Progress in Women’s Healthcare” (PPWH) programme – an incubator programme to support research capacity-building in LMIC’s – has launched its first project in Nagpur, India. Under the mentorship of Drs Tom Easterling and Gerda Zeeman and with the financial support from the Preeclampsia Foundation, “Ecology of Eclampsia: Study of structural, neurocognitive and socio-demographic determinants”, has commenced. This two-year programme will not only result in important information
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2014about eclampsia in the Nagpur region, but will also help train a
team in effective research methodology and execution.
The International Society for the Study of Hypertension in Pregnancy (ISSHP) and the Preeclampsia Foundation recently announced a collaborative program at the 2014 ISSHP World Congress to advance research in the field of hypertension in pregnancy. EMpowering Progress in Obstetric and Women’s hEalth Research (EMPOWER) creates and supports partnerships between seasoned investigators and young investigators in low resource settings to improve research capacity, primarily in the area of high blood pressure in pregnancy. This partnership will focus on pilot projects that have the potential to improve health outcomes from pre-eclampsia in the local population. The secondary objective of EMPOWER is to disseminate those results and advocate for required resources to the broader maternal health community, other funders, professional societies and governments. The Preeclampsia Foundation would be providing the financial seed money to enable execution of the research. In low-resource countries, developing a research programme has the potential to positively impact the broader community, as well as directly impact the clinical care and lessen the threat of pre-eclampsia to those mothers and babies.
Although not a low resource setting, the Foundation partnered with officials, industry and academia in Ireland to launch that country’s first Pre-eclampsia Awareness Day on 2 July 2014. Significant media coverage resulted, including an outpouring of support from women in the US and beyond, demonstrating an interest in raising global awareness.
The Preeclampsia Foundation continued to work with global partners to ensure that pre-eclampsia information is available through already established channels. Examples include BabyCenter.com, Women Deliver, Every Mother Counts, and Lamaze International. Periodically, random requests and opportunities present themselves that we seek to support however possible. For instance, Anthony, in Kenya, lost his business, his friends, and relatives. He was shunned by all because they believed his wife’s eclamptic seizures were the result of dabbling in witchcraft. She has had lasting medical problems and he is trying to raise his daughter essentially alone. He is planning to do a walk across the country to raise awareness and funding to build a community hospital staffed by knowledgeable care providers. While this may seem implausible, there is no limit to what dedicated individuals can accomplish!
www.preeclampsiaregistry.org
Since the Preeclampsia Registry™ was launched by the Preeclampsia Foundation in September 2013, the online patient and family database for those affected by pre-eclampsia and related hypertensive disorders of pregnancy has enrolled more than 1,000 participants from around the world. It has also been accepted into the Global Pregnancy CoLaboratory, an initiative funded by the Bill & Melinda Gates Foundation as part of PRE-EMPT. Collection of medical records has begun in earnest and a recently awarded medical research grant will allow for creation of the biobank (DNA) portion of the Registry within the next 12 months. The Preeclampsia Registry includes all of the core data variables recommended by CoLab and the Women’s Health Registries Alliance, is overseen by a commercial IRB, has been developed by MedSciNet, a leader in obstetric research database development, and is advised by a diverse group of scientific advisors.
Three studies are already underway using the Preeclampsia Registry and preliminary results of one were shared via a poster presentation at ISSHP (Oct. 2014).
www.preeclampsia.org/es
During the last 12 months, nearly 1.4 million individuals visited our website, www.preeclampsia.org. This audience accessed the website from 223 nations, including low and middle income countries.
In June of 2014 we upgraded the website to optimize it for mobile accessibility and to add Spanish content. For most of the world, mobile access to Internet-based information is a primary need. We also “transcreated” or translated much of our patient education materials, both print and online, into Spanish for the launch of a Spanish version of the mobile website in July of 2014. Although we anticipate this serving the portion of US population that are Spanish speakers, we are especially eager to support pre-eclampsia awareness and education in Central and South America with this content, where pre-eclampsia is the #1 leading cause of maternal mortality. We are currently working with volunteers interested in advancing outreach to Hispanic and Latina women, but are also seeking to fund a permanent staff position that will drive multimedia outreach and community building.
Patient Education Tools
During the last 12 months, we also promoted and made widely available our Illustrated Signs and Symptoms tear pad, an evidence-based pictorial education tool.
A recent US-based market survey also found 83% percent of today’s expectant and very recently delivered mothers are aware of pre-eclampsia as a serious complication of pregnancy. However, less than half of them knew what signs and symptoms needed to be reported. As a result, an animated “explainer video” was produced and shared out via multiple communication partners, including the state of Florida’s Public Health Department’s online toolbox. The English version already has more than 12,000 views, more than 3,000 for the Spanish version.
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Picture 20: Screenshot of the animated “explainer video” with signs and symptoms of pre-eclampsia. This video is available in both English and Spanish, and was produced and shared out via multiple communication partners, including the state of Florida’s Public Health Department’s online toolbox.
This year, the Preeclampsia Foundation provided nearly 20,000 educational tools to clinicians and hospitals for their patients in the United States and beyond. Included among them are our Pre-eclampsia FAQ brochure, Pre-eclampsia and Heart Disease brochure, HELLP Syndrome brochure, and Illustrated
Signs and Symptoms tear pad, and several videos. We continue to promote the availability of these materials in English and Spanish via www.preeclampsia.org.
Supporting WHO and Other Task Forces
Other activities included our participation on two World Health Organization (WHO) task forces to identify maternal research priorities for 2015–2025, and with Merck for Mothers to prioritise development and implementation priorities in pre-eclampsia for the next three to five years.
In the US, a growing focus on maternal mortality and morbidity has allowed the Foundation’s advocacy work to impact patient needs in this process. The National Partnership for Maternal Safety includes a task force that is developing guidance around supporting women and families who have suffered from bad outcomes in hypertensive pregnancies. The recent practice guidelines that the Preeclampsia Foundation helped the American College of Obstetricians & Gynecologists develop will prove very helpful to ensure that a basic level of quality care is provided to every woman, everywhere.
YEAR FIVE ANTICIPATED DELIVERABLES
The Preeclampsia Foundation will continue to work to enhance patient advocacy and education; including enhancement of the Preeclampsia Registry to enroll diverse populations. The second year of PPWH project in India will be completed.
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2014GLOBAL LIBRARY OF WOMEN’S
MEDICINE HDP TEXTBOOKEditors-in-Chief: Laura Magee & Peter von Dadelszen
Partners: David Bloomer & Paula Bloomer (GLOWM/Sapiens
Publishing)
Funding: The Sabrina’s Foundation
In the context of the hypertensive disorders of pregnancy (HDP; pre-eclampsia, gestational hypertension and pre -existing hypertension), the knowledge-to-action gap is that gulf between the burgeoning knowledge-base to provide evidence-based guidance and care to women in high income countries and the disparate relevance of guidance, resources, and cultural context in low and middle income countries (LMICs). We have designed a strategic set of tools that will be provided free to LMIC-based professionals, women and their families; some of these tools will be developed in 11 languages to improve global outreach.
Under the aegis of the Society of Obstetricians and Gynaecologists of Canada (SOGC), we have published updated, evidence-based guidelines for the diagnosis and management of the HDP. These guidelines build on an established track record of the 1997 and 2008 iterations that led the way in setting the international standard for HDP guidelines. Clearly, these guidelines have been developed for the Canadian context of a well-resourced health care system. In parallel, British, Dutch, American and Australasian colleagues have produced HDP guidelines that inform best evidence-based care.
The Global Library of Women’s Medicine (GLOWM [http://www.glowm.com/]), and associated publishing house, Sapiens, provides medical professionals worldwide with open access, expert, peer-reviewed, guidance on best practice for women’s medicine. The site focusses on safer motherhood by offering a range of resources to support doctors, midwives and community health care providers, especially in LMICs, where access to the latest information is not consistently and readily available. GLOWM/Sapiens has produced both a textbook and related online materials dedicated to improving the diagnosis and the management of the leading cause of maternal death, postpartum haemorrhage (PPH). This textbook, now in its second edition, is published and distributed free-of-charge to colleagues in LMICs, with full cost recovery from those in high-income countries. In addition, there is open online access to the PPH textbook as a series of pdfs. The textbook has set the international standards for the diagnosis and management of PPH.
The International Federation of Gynecologists and Obstetricians (FIGO) is the global organisation that groups obstetricians and gynaecologists, with member associations in 125 countries/territories. Its Secretariat is based in London, UK. FIGO’s mission is to promote the wellbeing of women and to raise the standards of practice in obstetrics and Gynecology. It is a benevolent, non-profit organisation funded through subscriptions received from member societies, grants and the proceeds of its triennial World Congress. FIGO has signed a
memorandum of understanding with GLOWM to use it as its educational platform for members from all national societies.
Using an integrated knowledge translation approach, we aim to:
• Use the ADAPTE and AGREE II (Appraisal of Guidelines Research and Evaluation II) instruments to review relevant guidelines to inform textbook and associated toolkit content, including engagement with global partners (http://www.g-i-n.net/activities/adaptation).
• Modify existing guidance for LMIC relevance, and to publish the textbook and a textbook of online resources and other materials for global distribution.
• Use reverse innovation to inform health care provision in rural and remote Canada.
PRE-EMPT ADVOCACY, GLOBAL ACCESS AND SELECT PUBLICATIONS
PRE-EMPT has used multiple strategies to advocate at national and international levels for improved awareness and outcomes related to pre-eclampsia and eclampsia.
1. POLICYMAKERS
The objective of the PRE-EMPT project- to develop, test and introduce new knowledge that will reduce the un- acceptable maternal, perinatal, family, societal, and global impacts of pre-eclampsia, and the other hypertensive disorders of pregnancy. The impetus behind, and focus of, the PRE-EMPT group is to identify cost-effective interven- tions that can be scaled up, and sustained, across low and middle-income settings.
Should pre-pregnancy calcium supplements reduce the incidence of both pre-eclampsia and its associated ad- verse maternal and perinatal consequences (Objective 1), these data will support a focused effort to improve dietary calcium intake, resulting in population-level improvements in health and health outcomes. Task-shifting and improv- ing the capacity of women’s immediate caregivers (e.g., community health workers) to identify pre-eclampsia and to respond through community- and primary health centre-based mechanisms of triage, transport, and treatment (Objectives 2 & 3) will have an important, and beneficial, impact on maternal and perinatal survival, with consequent economic and societal benefits. The CLIP package itself is low cost, and the results of Objective 3 will place us in the position to test its impact in a definitive cluster RCT. Tomorrow’s low cost and innovative interventions will derive, in part, from the aligned efforts of the Global Pregnancy CoLaboratory (Obj 4). Evidence-based WHO guidelines (Objective 5) provide the basis of care in many LMICs, and are used to justify requests for support of maternal, newborn and child health initiatives from governments and agencies.
The CLIP package of care comprises of a combination of evidence-based interventions; and thus to understand implementation issues, it is imperative to understand the context of where CLIP will be employed. Furthermore, it is important to recognise that components of the CLIP package of care target multiple individual, group and organisation levels and may consist of tasks that need support from all these levels to achieve objectives, such as task-shifting to cHCP roles or administration of injections in the community. We have endeavoured to include policy makers at the earliest possible stages of project planning. The first objective of the CLIP Feasibility study, focussed on “Obtaining Key Stakeholder support for the CLIP cRCT”, has been carried out in Nigeria, Pakistan and India and Mozambique. These key stakeholders have been identified in collaboration with
the CLIP site PIs, and include the state chapters and national societies of obstetricians and gynaecologist’s, cHCPs professional association and programmes, maternal-child health programmes, district and facility health organisation leads, provincial Ministries of Health, and other identified relevant key stakeholders. Through individual interviews, focus group discussions and site visits, we have engaged the Societies of Obstetricians & Gynaecologists and medical officer leads at referral centres. The CLIP team has met individuals in clinical facilities, and presented at obstetric grand and/or sign-over rounds upon their invitation.
A crucial element of the CLIP Feasibility Study has been to be able to identify potential beliefs and attitudes that may impact the CLIP study. These, along with barrier assessment to identify potential barriers to project success and/or stakeholder support and commitment to CLIP, have been undertaken to modify the CLIP cRCT in each site.
In addition, through the PRE-EMPT collaboration we help many of our partner centres in Nigeria, Mozambique, Pakistan and India, to name a few, take the next step towards sustainable academic activity. Focussed global efforts during the past decade have proven that significant progress is possible: the number of women who die each year during pregnancy or childbirth has dropped substantially from 523,000 deaths in 1990 to 289,000 in 2013; and the global number of deaths among children younger than five has decreased from more than 12 million in 1990 to 6.6 million in 2012. Despite these achievements, more work needs to be done. Together, we can eliminate preventable deaths among women, children and newborns, and save the millions of lives that hang in the balance.
Picture 21: Lamp lighting ceremony during the CLIP Pilot Trial launch in India.
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Picture 22: Hon Dr Olaokun Soyinka, the Commissioner for Health of Ogun, with Peter von Dadelszen (centre) and a cross section of stakeholders at the CLIP Launch at Obas Complex, Governor’s Office Abeokuta, Nigeria.
Picture 23: A meeting with the key stakeholders was held on 28 January 2014 at the Indus Hotel Hyderabad. Key participants of the meeting were Mr. Iqbal Hussain Durrani (Secretary Health, Sindh), Dr. Ashfaque Memon, (DG Health, Sindh), Dr. Rahat Qureshi (Principal Investigator, CLIP Trial), Dr. Aftab Munir (ISRA Univeristy) and Dr. Sajid Soofi (Aga Khan University).
PRE-EMPT and the Canadian Network for Maternal, Newborn & Child Health (MNCH)
The Canadian Network for MNCH (CAN-MNCH) was established following the Roundtable on the Muskoka initiative in November 2010, hosted by the Canadian Minister of International Cooperation. PRE-EMPT is a part of this Network along with 70 other Canadian organisations who are actively engaged in MNCH work in over a thousand regions around the world. The PRE-EMPT project establishes Canada as a key player in its global efforts to accelerate progress on maternal health.
Saving Every Woman Every Child, funded by the Government of Canada
PRE-EMPT has been actively engaged with the Canadian Network for Maternal, Newborn & Child Health in the ‘Saving Every Woman Every Child” movement, undertaken with the financial support of the Government of Canada. Canada hosted a high-level summit on Maternal, Newborn and Child Health from 28–30 May 2014 in Toronto, Canada. Prime Minister Stephen Harper invited Canadian stakeholders and experts including members of the PRE-EMPT team as well as global leaders from developing countries, civil society, development donors, the private sector and foundations to work together so that continued progress can be made. Peter von Dadelszen, Principal Investigator of PRE-EMPT, Tabassum Firoz, Co-Principal Investigator of MOM (Mapping Outcomes for Mothers), Mark Ansermino, co-Principal Investigator of PIERS On the Move, Zulfiqar Bhutta (co-Principal Investigator of the CLIP trial) and Tom Walker (CEO of LionsGate Technologies) were invited to the high level summit. PRE-EMPT members helped build consensus around scaling-up progress on maternal, newborn and child health, reducing newborn mortality, and building new partnerships with the private sector to leverage innovation and financing.
Picture 24: Peter von Dadelszen (far right) and Tom Walker (far left) showcase the Phone Oximeter to Justin Trudeau, Leader of the Liberal Party of Canada, his wife, Sophie Grégoire and Helen Scott from the CAN-MNCH, the event hosts.
Commodity Security : PRE-EMPT and UN Commission on Life-Saving Commodities for Women and Children (Maternal Health Technical Resource Team, MHTRT)
As part of the Every Woman Every Child movement (EWEC), the UN Commission on Life-Saving Commodities for Women and Children (UNCoLSC) has identified 13 overlooked life-saving commodities that, if more widely accessed and properly used, could save the lives of more than six million women and children. Three of the 13 commodities identified by the UNCoLSC as essential commodities are used to treat and address the leading causes of death during pregnancy and childbirth: oxytocin and misoprostol to treat postpartum hemorrhage (PPH), and magnesium sulfate to prevent and treat eclampsia. By increasing the availability of these three key medicines, maternal mortality from PPH and eclampsia – which account for more than half of all maternal deaths globally – could be reduced by 1.4 million over ten years.
However, despite evidence supporting the widespread use of these medicines, a number of barriers affect availability, accessibility, affordability, quality, and use. The concept of commodity security (CS), broadly defined as the ability to obtain and use health commodities when and where they are needed, is one that has proven successful in identifying the gaps in access to groups of commodities and, subsequently, to the development of strategic plans to address them. A similar, category-specific focus on maternal health commodities is needed by policymakers and implementers so they can better understand evaluate, and design solutions based on the unique characteristics of the commodities.
Along with members of the JSI Research & Training Institute, PRE-EMPT team members—Tabassum Firoz and Sumedha Sharma were involved in data abstraction, analysis and writing of white paper that proposes a framework for maternal health commodity security (MHCS) based on an integrated health system strengthening approach to improving availability, accessibility, and affordability.
The objectives of the White Paper are to:
• Describe the aim and 12 key components of the MHCS Framework.
• Consider the barriers and facilitating factors of each of the components of the MHCS Framework.
• Examine the commodity specific issues for the three key maternal health commodities.
• Identify and discuss recommendations culled from emerging themes.
The MHCS Framework is based on the assumption that health system strengthening is the means through which MHCS is achieved, and improved maternal health is the outcome of system improvements that specifically address MH supplies. The situation for MHCS may be improved by focusing on
strengthening the health system—the organisations, service delivery capacity, infrastructure, people, and resources that support equitable access to and rational use of key maternal health medicines.
The components of the MHCS framework parallel health system organisation by grouping elements at the 1) macro; 2) meso; and 3) micro levels. At the macro level, the framework refers to the overarching architecture of the health system and its high level stakeholders and decision-makers. It includes elements such as policies and regulations, coordination, financing, and advocacy and leadership. Stakeholders at the macro-level make decisions about the health system that inform the design, financing, and rights of beneficiaries of the system. Decisions made at the macro level are transformed into programmes at the meso level. The programmes are shaped by organisational and managerial decisions that consider service delivery, human resources, health supplies, supply chain strengthening, quality assurance, monitoring and evaluation. The micro level focusses on the way individuals—such as patients and providers—and families behave, communicate, and make day-to-day decisions. This level includes population awareness.
Citation for the White Paper:
JSI Research & Training Institute, Inc. and University of British Columbia 2014. A Commodity Security Framework for Maternal Health. Arlington, Va.: JSI Research & Training Institute, Inc., for the UN Commission on Life-Saving Commodities for Women and Children, Commodity Security Working Group of the Maternal Health Technical Reference Team.
Evidence-based guidelines
Drs Peter von Dadelszen, Laura Magee, Tabassum Firoz, Jennifer Hutcheon, and Anouk Pels of the PRE-EMPT group, part of the Canadian Hypertensive Disorders of Pregnancy group, co-authored the guideline that summarizes the quality of the evidence to date and provides a reasonable approach to the diagnosis, evaluation and treatment of the hypertensive disorders of pregnancy (HDP). An abbreviated version of this guideline is now published in the JOGC. (Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary. Magee LA, Pels A, Helewa M, Rey E, von Dadelszen P; SOGC Hypertension Guideline Committee. J Obstet Gynaecol Can.2014 Jul;36(7):575–6. The full document is published in Pregnancy Hypertension 2014; 4(2):105-145.
The literature reviewed included the previous Society of Obstetricians and Gynaecologists of Canada (SOGC) HDP guidelines from 2008 and their reference lists, and an update from 2006. Medline, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Registry of
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Reviews of Effects (DARE) were searched for literature published between January 2006 and March 2012. Articles were restricted to those published in French or English. Recommendations were evaluated using the criteria of the Canadian Task Force on Preventive Health Care and GRADE.
2. SCIENTIFIC COMMUNITY
Picture 25: Laura Magee joined international experts to discuss diagnostic criteria for pre-eclampsia at the ISSHP World Congress 2014 in New Orleans, USA.
Over the November 2013–November 2014 period, scientifically, we have published:
A risk prediction model for the assessment and triage of women with hypertensive disorders of pregnancy in low-resourced settings: the miniPIERS (Pre-eclampsia Integrated Estimate of RiSk) multi-country prospective cohort study.
Payne BA, Hutcheon JA, Ansermino JM, Hall DR, Bhutta ZA, Bhutta SZ, Biryabarema C, Grobman WA, Groen H, Haniff F, Li J, Magee LA, Merialdi M, Nakimuli A, Qu Z, Sikandar R, Sass N, Sawchuck D, Steyn DW, Widmer M, Zhou J, von Dadelszen P; miniPIERS Study Working Group. PLoS Med. 2014 Jan;11(1):e1001589. doi: 10.1371/journal.pmed.1001589. Epub 2014 Jan 21. PMID:24465185
Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary.
Magee LA, Pels A, Helewa M, Rey E, von Dadelszen P; Hypertension Guideline Committee. J Obstet Gynaecol Can. 2014 May; 36(5):416–41. English, French. PMID: 24927294
Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy.
Magee LA, Pels A, Helewac M, Reyd E, von Dadelszen P, On behalf of the Canadian Hypertensive Disorders of Pregnancy (HDP) Working Group. Preg Hypertension. 2014 April; 4(2):105-145. DOI: 10.1016/j.preghy.2014.01.003
Low-dose calcium supplementation for preventing pre-eclampsia: a systematic review and commentary.
Hofmeyr GJ, Belizán JM, von Dadelszen P; Calcium and Pre-eclampsia (CAP) Study Group. BJOG. 2014 Jul;121(8):951–7. doi: 10.1111/1471–0528.12613. Epub 2014 Mar 13. Review. PMID: 24621141
Strategy for standardization of pre-eclampsia research study design
Myatt L, Redman CW, Staff AC, Hansson S, Wilson ML., Laivuori H, Poston L, Roberts JM et al. Hypertension. 2014;63(6): 1293–301.
Magnesium sulphate for the management of pre-eclampsia and eclampsia in low and middle income countries: a systematic review of tested dosing regimens.
Gordon R, Magee LA, Payne B, Firoz T, Sawchuck D, Tu D, Vidler M, de Silva D, von Dadelszen P. J Obstet Gynaecol Can. 2014 Feb;36(2):154–63. Review. PMID: 24518915
Pre-eclampsia: an update.
von Dadelszen P, Magee LA. Curr Hypertens Rep. 2014 Aug;16(8):454. doi: 10.1007/s11906–014–0454–8. PMID: 24915961
Oral antihypertensive therapy for severe hypertension in pregnancy and postpartum: a systematic review.
Firoz T, Magee L, MacDonell K, Payne B, Gordon R, Vidler M, von Dadelszen P; the Community Level Interventions for Pre-eclampsia (CLIP) Working Group.
BJOG. 2014 Sep;121(10):1210–1220. doi: 10.1111/1471–0528.12737. Epub 2014 May 16. PMID: 24832366
Uric acid as a predictor of adverse maternal and perinatal outcomes in women hospitalized With preeclampsia.
Livingston JR, Payne B, Brown M, Roberts JM, Côté A-M, Magee LA, von Dadelszen P; for the PIERS Study Group. J Obstet Gynaecol Can 2014;36(10):870–877.
Development of mHealth applications for pre-eclampsia triage
Dunsmuir, D, Payne, B, Cloete, G.; Petersen, C, Gorges, M, Lim, J, von Dadelszen, P, Dumont, G, Anersmino, JM. IEEE J Biomed Health Inform. 2014 Nov;18(6):1857-1864. PMID: 25375683
3. PATIENTS AND THE GENERAL PUBLIC
Community engagement involves the collective action of individuals, families, religious leaders, policy makers, health care providers and community members toward the creation of meaningful and sustainable change and plays an instrumental role in the CLIP trial. Studies indicate that successful health behaviour change occurs when interventions create positive social, individual, and environmental conditions. Furthermore, community-based interventions that include women’s and men’s support groups, education, counselling, home visits, emergency transport initiatives and fundraising activities, have shown significant improvements in maternal and perinatal morbidity and mortality.
For each of the CLIP trials, a community engagement strategy is being used with the participation of local stakeholders including community leaders, the women of the communities themselves, and their mothers, husbands, and mothers-in-law, regarding pre-eclampsia, its origins, symptoms, signs, and potential consequences, pre-permissions for maternal transport, and fundraising activities around transport and treatment costs. The community engagement strategies are culturally and contextually appropriate, meaningful and sustainable, and effective in improving maternal health in CLIP intervention communities.
Some strategies for community engagement include: 1) education around identification of warning symptoms and signs of pregnancy complications, particularly pre-eclampsia & eclampsia by relating the association of danger symptoms/signs with the occurrence of pre-eclampsia/eclampsia and using the warning symptoms of pre-eclampsia and eclampsia pictograms; (2) permission for women to seek care by recognise the need for decision-making power and/or prior permissions in the event of obstetric emergencies; (3) identification of skilled birth attendant; (4) identification of facility for delivery; (5) arranging/preparing transport and treatment; (6) creating feedback mechanisms about adverse outcomes and ‘great saves’; (7) discussion to address the
barriers identified in the country-specific CLIP Feasibility Study.
The CLIP Feasibility Study has highlighted some solutions to some perceived barriers, which includes engagement of the community at various levels. For instance, a crucial piece in the CLIP Pakistan Trial is to engage male decision makers so that women may obtain the necessary advance consents for immediate care transport to a health care facility in case of emergency.
Picture 26: An example of the community health education materials used in the CLIP Pakistan Trial.
4. INDUSTRY COLLABORATION
PRE-EMPT has established collaborations with industry to foster innovation in global health, and to develop and share new knowledge and expertise.
Our three most notable partnerships include:
1. The Phone Oximeter, with LionsGate Technologies, Vancouver
The Phone Oximeter, devised by LionsGate Technologies, is a device that uses a probe attached to a patient’s fingertip to measure oxygen saturation in the blood; the data are then relayed to a mobile phone, tablet or
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the predictive ability of the miniPIERS model and has huge significance for task-shifting, especially in resource-constrained settings. We hope to test the Phone Oximeter in Mozambique and Pakistan during the CLIP trials. With pulse oximetry added to the miniPIERS in the PIERS On the Move application, community healthcare workers in low resource settings can achieve sound clinical decision making power and then take steps to help the patient; they can administer medication and arrange urgent transportation for definitive care at a larger health care facility if needed. The addition of the Phone Oximeter is being supported by a crowd-sourcing campaign called the “Sensor Project”.
2. Microlife BP Device
The King’s College London CRADLE research group, in collaboration with Microlife, has previously developed a semi-automated BP device (Microlife 3AS1–2) specifically for use in LMICs. It can be manufactured at low cost (<$20/piece) and the manual inflation means that battery supply is only used to power the display showing the BP readings. The primary objective of phase two of the CRADLE project is to develop an accurate and tested low-cost solution to improve antenatal detection of pre-eclampsia, and shock associated with PPH and sepsis, by adapting existing tools for BP measurement for use by frontline health care providers working at a community level and in first-level clinics, who are best placed to both access pregnant women and initiate life-saving interventions. Equipping frontline health workers with novel technology such as this, as well as provision of basic training in its use, enhances their capabilities and performance. Once widely implemented in LMICs, the availability of BP measurements will facilitate referrals of high-risk women to secondary level centres and thereby has potential to improve pregnancy outcome for both the mother and infant.
3. Alere
The von Dadelszen laboratory has been collaborating with Alere International since 2008. Alere, formerly Inverness Biomedical, is a diagnostics company with an established record in point-of-care diagnostics. In terms of pre-eclampsia and fetal growth restriction science and diagnostics, Alere continues to be a vital partner as we seek to develop, test and implement point-of-care diagnostics that will identify the ‘sick’ placenta so that antenatal and intrapartum resources can be focussed on women with pregnancies most at risk for adverse maternal and perinatal outcomes,
especially in less developed economies where such resources are scarce. In this year’s annual report we have described two such collaborations related to intrauterine growth restriction, the placental growth factor study and the Canadian STRIDER trial.
PARTNERSHIPS
APPENDIX A – SUMMARY OF SITE VISIT AND INITIAL FEASIBILITY STUDY FINDINGS
Partnerships
The following stakeholders have been engaged and have provided support for the trial:
Nigeria – Academic
Centre for Research in Reproductive Health, Sagamu, Ogun State, Nigeria.
Nigeria – Regional & national
Commissioner of Health, Ogun State; Ogun State Ministry of Health; Olabisi Onabanjo University Teaching Hospital; Medical Officers of Health, Ogun State LGAs; Society of Gynecology and Obstetrics of Nigeria (SOGON); Association of Maternal and Fetal Medicine Specialists of Nigeria; Yewa South Local Government (Ilaro State Hospital, Leysley PHC, Igbo-gidi PHC); Remo North Local Government (General Hospital, Isara, Ode-Remo PHC, Ipara PHC, Idi-Aba Health Post; Sagamu Local Government (Ogijo PHC, Sagamu LGA) and Imeko Local Government (General Hospital, Imeko, Imeko PHC).
Mozambique – Academic
Eduardo Mondlane University, Maputo, Mozambique.
Mozambique – Regional & national
Mozambique Ministry of Health; Maputo Municipal Council (responsible for health); Mozambique Association of Obstetricians and Gynecologists (AMOG); Eduardo Mondlane University, Maputo; Maputo Central Hospital; Clinton Foundation.
Pakistan – Academic
Aga Khan University and Jinnah Postgraduate Medical College, Karachi, Pakistan.
Pakistan – Regional & national
Sindh Ministry of Health; National Lady Health Worker Programme; Society of Obstetricians and Gynaecologists of Pakistan; Isra University Hospital; Liaquat University Medical Health Sciences Hospital; Aga Khan Maternal & Child Care Centre, Hyderabad; Taluka Headquarter Hospital; Aga Khan University Hospital, Karachi; Jinnah Postgraduate Medical College Hospital, Karachi.
India – Academic
Jawaharlal Nehru Medical College, Karnataka Lingayat Education University, Belgaum, India; S Nijalingappa Medical College, HSK (Hanagal Shree Kumareshwar) Hospital and Research Centre, Bagalkot, India.
India – Regional & national
District Health Officers, Belgaum and Bagalkot; Chief Executive Officer, Zilla Panchayat (local self government), Belgaum and Bagalkot; Programme Director, RCH, Ministry of Health and Family Welfare, Government of Karnataka, Bangalore; Reproductive Health and Nutrition Division, Indian Council of Medical Research, New Delhi; Representatives of Federation of Obstetric and Gynaecological Societies of India (FOGSI) and Indian Academy of Paediatrics (IAP).
World Health Organization Department of Maternal, Newborn, Child and Adolescent Health (MNCAH)
The chair of the PRE-EMPT objective 5 (knowledge translation) group is Dr Matthews Mathai, from this WHO department. The MNCAH group was instrumental in co-ordinating the development of the 2011 WHO pre-eclampsia guidelines, and will be instrumental in updating the guideline to reflect the findings of the CLIP trial, and in promulgating the results of the CLIP trial to key decision makers in LMICs. Dr Lale Say is a member of the advisory group advising on maternal mortality and morbidity methods for CLIP.
UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (RHR)
The WHO RHR group have been important partners in the PIERS research agenda (Mario Merialdi and Mariana Widmer), as well as for objectives 1 (Ana Pilar Bertràn) and 5 (Metin Gülmezoglu) of the PRE-EMPT project.
USAID Maternal and Child Survival Program (MCS)
We have developed a partnership with MCHIP, and now its successor program MCS (Maternal and Child Survival
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member). MCHIP is the USAID Bureau for Global Health’s flagship programme focussed on maternal, neonatal and child mortality reduction and acceleration of progress towards MDGs 4 and 5. An element of MCHIP’s mandate is to strengthen the capacity of inpatient facilities in LMICs in terms of the use of evidence-based care. We will co-ordinate our activities in Nigeria, Mozambique, Pakistan, and India so that the MCHIP will support public and private facility capacity building in the referral centres in Nigeria (Sagamu), Mozambique (Manihça and Maputo), Pakistan (Matiari, Hyderabad and Karachi), and India (Belgaum and Bagalkot). This commitment of time, energy and expertise will ensure that women in the study clusters will receive timely and effective care in the centres to which they are referred.
Current practice—the provision of maternity care and pre-eclampsia interventions
Nigeria
Antenatal care is delivered at the primary health centre level. Most women attend antenatal care every 3–4 weeks up to 28 weeks gestation, every 2 weeks until till 36 weeks gestation and weekly thereafter. A typical antenatal visit does include blood pressure measurement and proteinuria testing by indication. Few clinics have a laboratory or ultrasound capacity. Most of obstetric services are paid out of pocket. Few PHCs have ambulance services for referral of complex cases.
Community Health Extension Worker (CHEW) and Health Assistants (HA) training & current scope of practice
Community Health Extension Workers (CHEW) and Health Assistants (HA) are responsible for delivery of primary health care services in Nigeria. They work both in the community and clinic settings; however due to workload restraints CHEWs often remain stationed predominantly at the PHC. The training and regulation of practice is under the jurisdiction of Community Health Practitioners’ Registration Board of Nigeria. The CHEW programme includes certification in community health, practical exercises and examinations, supervised clinical experience and supervised community experience. The areas of focus for CHEW training relevant to CLIP are: English training, computer education, medical sociology, reproductive health, clinical skills, and referral system and outreach services. The current CHEW curriculum does not include specific training for management or diagnosis of pre-elcampsia/eclampsia or any other pregnancy complication.
Mozambique
The Mozambique health system is largely supported by foreign aid. There are significant human resource shortages which require task shifting for obstetric care services. Countrywide, there is a low number of a available skilled birth attendants. Access to primary health care facilities, where antenatal care is delivered, is also low. The first antenatal visit is typically delayed until the 2nd or 3rd trimester, with 84% coverage for at least one antenatal visit during pregnancy 57. As a result of these constraints the majority of births are rural many without skilled attendants.
Magnesium sulphate has long been used in Mozambique for the management of pre-eclampsia and eclampsia, however, its use has been primarily at central hospitals and alternative anti-seizure medications have been used in the periphery.
Agente Polivalente Elementares (APEs) training & current scope of practice
Agente Polivalente Elementares (APEs) (or basic multi-task health care helpers) help to promote health in their communities; constituting the link between them and the national health system. APEs are recruited from within the community and receive six months’ training to provide basic preventive (community health education) and curative community based-care for diarrhoea, pneumonia and malaria, focussing on the widespread use of diagnostics and appropriate treatment. The APEs allow isolated populations to have access to basic health care and essential drugs for high burden diseases like malaria, and act as an entry point for referral to higher level health services, providing basic first aid before transfer where needed.
India
The Government of India has recently committed to the National Rural Health Mission. This initiative aims to obtain universal skilled birth attendance across the country. The National Rural Health Mission highlights the role of ANMs in providing antenatal care, timely referrals, and provision of treatment in emergency obstetric cases. Health care workers providing obstetric care at the community level are ANMs, ASHAs and Anganwadi (AWW) Workers. Each antenatal visit should include: a medical history, physical exam, abdominal exam, laboratory investigations, clinical interventions (IFA supplement, tetanus toxoid injection, malaria), and health promotion counselling. A minimum of four antenatal visits for all pregnancies is encouraged: before 12 weeks, 12–26 weeks, 28–34 weeks and 36 weeks-term.
Facilities are generally equipped to manage cases of pre-eclampsia and eclampsia. Due to concerns regarding safety and availability diazepam is frequently used in place of MgSO4.
Auxiliary Nurse Midwife (ANM) training & current scope of practice
Training for Assistant Nurse Midwives (ANM) includes a wide range of health competencies: understanding of holistic health/social determinants of health, ability to mobilise communities, provide emergency care, treatment of minor ailments, midwifery services and referral, basic neonatal care and referral, child services, guide and train TBAs and AWWs, health counselling, participate in national programmes, collaborate with community organisations, manage health care settings. Their midwifery services include care during pregnancy, intrapartum and postpartum.
ANMs are expected to measure blood pressure at every visit and test for protein in the cases of high blood pressure. If a woman is identified with high blood pressure the ANM is responsible for referral to a 24 hour PHC to initiate antihypertensive therapy. ANMs also follow-up and advise of the warning symptoms. In cases of eclampsia the ANM should ensure safety, give MgSO4 (10g i.m.) and refer to a facility within two hours.
Accredited Social Health Activist (ASHA) training & current scope of practice
ASHAs are local women trained to act as health educators and promoters in their communities. They receive a total period of 28 days’ training in five episodes. However, this core training is supplemented by ongoing CPD activity in parallel with the development of necessary skills and expertise through on the job training. After a period of 6 months of functioning in her village, she is then sensitised to issues related to HIV, AIDS, and STIs (prevention and referral), as well as trained on newborn care.
Their tasks include motivating women to have a facility birth, bringing children to immunisation clinics, encouraging family planning, treating basic illness and injury with first aid, keeping demographic records, and improving village sanitation. In addition, ASHAs are central to communication between the health care system and rural populations.
Pakistan
Pakistan’s public health system is centralized under the Federal Government and provincial Health Ministries. The public health sector employs LHWs and Lady Health Visitors (LHV) in rural sectors and nurses and doctors in health facilities and hospitals. According to the 2008 Demographic and Health Survey: Pakistan, less than 30% of women receive four antenatal visits during pregnancy. In many rural settings, staffing levels are inadequate and referral systems function poorly. Almost 70% of births take place at home, usually attended by a Dai (traditional birth attendant [TBA]). Rural and urban public facilities provide free consultation for obstetric care, whereas consultation charges in private facilities range from $0.5–3USD in rural areas and $4–16USD in urban areas. Some public and private facilities
provide ambulance services, additional ambulance services are provided by non-profit organisations in some regions. The majority of health facilities in Hydrabad and Matiari do not have protocols/guidelines for managing pre-eclampsia and eclampsia. There is awareness of MgSO4 for the management of pre-eclampsia and eclampsia; however, many continue to use diazepam.
Lady Health Worker (LHW) training & current scope of practice
The Lady Health Worker Programme commenced in 1994 and currently employs 96000 LHWs as part of the federal healthcare system. Each LHW has to cover a population of around 1000–1500 individuals. This existing number of LHWs is insufficient as WHO suggests the requirement of 150,000 LHW’s to cater to the country’s health care needs.9 The Government of Pakistan is the major contributor to the funds for this programme, external sources only contribute around 11% of the total amount. The role of LHWs is pivotal in Pakistan’s health care system. They have 15 months of training in MCH. The LHW role in antenatal care includes: health promotion, hospital referrals, and basic neonatal care. Currently LHW is not responsible for immediate management of eclampsia /pre-eclampsia and refers such patients. LHW don’t carry any antihypertensive medicine for pregnant woman, and don’t have BP apparatus, their role was found to be limited ‘to advice to seek care from nearest referral facility’ in case if a pregnant woman complained about severe headache with dizziness. An external evaluation of the LHW programme concluded that it was effective in delivering family planning services and immunization services, in the management of diarrhoea, and, most recently through a cRCT, reducing the burden of stillbirth in Sindh Province.
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Appendix A: Steering Committee Members
PRE-EMPT
I. ACADEMIC STEERING COMMITTEE:
Co-Chairs: France Donnay & Peter von Dadelszen
Vice Chair: Sharla Drebit & Lee Pyne-Mercier
Objective Chairs and Vice Chairs:
• Zulfiqar Bhutta
• A. Metin Gülmezoglu
• Justus Hofmeyr
• Laura Magee
• Matthews Mathai
• Stephen Mujanja
• Beth Payne
• Chris Redman
• Jim Roberts
• Mandisa Singata
Technical Advisory Group:
• Wame Baravilala
• Zulfiqar Bhutta
• Simone Diniz
• Robert Goldenberg
• Michael Gravett
• Simon Lewin
• Lucilla Poston
• Shuchita Mundle
• Olufemi Oladapo
• Laura Reichenbach
• Donna Russell
• Jeffrey Smith
• Eleni Tsigas
• Jimmy Walker
• Charlotte Warren
• Beverly Winikoff
II. MANAGEMENT COMMITTEE
Co-chairs: France Donnay & Peter von Dadelszen
Vice Chair: Sharla Drebit & Lee Pyne-Mercier
Members: Jim Roberts
CAP
George Justus Hofmeyr Chair/PI University of Fort Hare and Witwatersrand University, South Africa
Stephen Munjanja Vice Chair/Site PI University of Zimbabwe, Zimbabwe
Mandisa Singata Vice Chair/Site PI University of Fort Hare and Witwatersrand University, South Africa
José Belizán Site PI Institute of Clinical Effectiveness and Health Policy Argentina
Eduardo Bergel Working Group Institute of Clinical Effectiveness and Health Policy Argentina
Ana Pilar Betrán Working Group World Health Organization
Sue Fawcus Site PI University of Cape Town, South Africa
Natalia Novikova Working Group/Co-ordinator
University of Fort Hare and Witwatersrand University, South Africa
Adegboyega Oyebago Site PI University of Witwatersrand, South Africa
Gabriela Cormick Working group Institute of Clinical Effectiveness and Health Policy Argentina
Jim Roberts Working Group University of Pittsburgh/Magee-Womens Research Institute, USA
Peter von Dadeslzen Working Group University of British Columbia, Vancouver, Canada
Tina Purnat Working Group World Health Organisation. Geneva, Switzerland
Sharla Drebit† Working Group University of British Columbia, Vancouver, Canada
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Beth Payne Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada and the CFRI Reproductive and Healthy Pregnancy Cluster.
Jennifer Hutcheon Department of Obstetrics and Gynecology, and, School of Population and Public Health, University of British Columbia, Vancouver, Canada and the CFRI Reproductive and Healthy Pregnancy Cluster.
J Mark Ansermino Department of Anaesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada
David R Hall Department of Obstetrics and Gynecology, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa
Shereen Z Bhutta Jinnah Post-graduate Medical College, Karachi, Pakistan
Christine Biryabarema Department of Obstetrics and Gynecology, Makerere University, Kampala, Uganda
William A Grobman Department of Obstetrics and Gynecology, Feinberg School of Medicine Northwestern University, Chicago, USA
Henk Groen Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
the late Farizah Haniff Department of Obstetrics and Gynecology, Colonial War Memorial Hospital, Suva, Fiji
Jing Li Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada and the CFRI Reproductive and Healthy Pregnancy Cluster
Laura A Magee Department of Obstetrics and Gynecology, and, School of Population and Public Health, and. Department of Medicine, University of British Columbia, Vancouver, Canada; CFRI Reproductive and Healthy Pregnancy Cluster.
Mario Merialdi Becton DickinsonFranklin Lakes, New Jersey
Annettee Nakimuli Department of Obstetrics and Gynecology, Makerere University, Kampala, Uganda
Ziguang Qu Department of Obstetrics and Gynecology and the CFRI Reproductive and Healthy Pregnancy Cluster
Rozina Sikandar Division of Women and Child Health, Aga Khan University, Karachi, Pakistan
Nelson Sass Department of Obstetrics and Gynecology, Universidade Federal de São Paulo, Maternidade de Vila Nova Cachoeirinha, Sao Paulo, Brazil
D Wilhelm Steyn Department of Obstetrics and Gynecology, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa
Mariana Widmer UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Training in Human Reproduction (HRP), Department of Reproductive Health and Research (RHR), Geneva, Switzerland
Jian Zhou Department of Obstetrics, Tongji University, Shanghai, P.R. China
miniPIERS
Peter von Dadelszen Department of Obstetrics and Gynecology, and, School of Population and Public Health, University of British Columbia, Vancouver, Canada and the CFRI Reproductive and Healthy Pregnancy Cluster.
CLIP Steering
CLIP EXECUTIVE COMMITTEE
Olalekan Adetoro Olabisi Onabanjo University Teaching Hospital, Sagamu, Nigeria
Zulfiqar Bhutta Aga Khan University Medical Center, Karachi, Pakistan
Mrutyunjaya B Bellad KLE University, Belgaum, India
Sharla Drebit University of British Columbia, Vancouver, Canada
Shivaprasad Goudar KLE University, Belgaum, India
Laura Magee University of British Columbia, Vancouver, Canada
Ashalata Mallapur KLE University, Belgaum, India
Beth Payne University of British Columbia, Vancouver, Canada
Rahat Qureshi Aga Khan University Medical Center, Karachi, Pakistan
John Obafemi Sotunsa Olabisi Onabanjo University Teaching Hospital, Sagamu, Nigeria
Marianne Vidler University of British Columbia, Vancouver, Canada
Peter von Dadelszen University of British Columbia, Vancouver, Canada
CLIP EXECUTIVE COMMITTEE
Mark Ansermino University of British Columbia, Vancouver, Canada
Ana Pilar Betrán World Health Organization, Geneva, Switzerland
Guy Dumont University of British Columbia, Vancouver, Canada
Susheela M. Engelbrecht PATH, Seattle, USA
Veronique Filippi London School of Hygiene and Tropical Medicine, London, UK
Tabassum Firoz University of British Columbia, Vancouver, Canada
William Grobman Northwestern University Medical School, Chicago, USA
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CLIP EXECUTIVE COMMITTEE
Marian Knight University of Oxford, Oxford, UK
Ana Langer Harvard School of Public Health, Boston, USA
Simon Lewin Norwegian Knowledge Centre for the Health Services, Oslo, Norway
Gwyneth Lewis University College London, London, UK
Craig Mitton Vancouver Coastal Health Research Institute, Vancouver, Canada
Olufemi Oladapo World Health Organization, Geneva, Switzerland
Nadine Schuurman Simon Fraser University, Burnaby, Canada
Andrew Shennan Kings College London, London UK
Joel Singer University of British Columbia, Vancouver, Canada
Jim Thornton Nottingham City Hospital, Nottingham, UK
WHO KT WORKING GROUP
Mattews Mathai WHO, Geneva, Switzerland
A. Metin Gülmezoglu WHO, Geneva, Switzerland
João Paulo Dias De Souza WHO, Geneva, Switzerland
Simon Lewin Norwegian Knowledge Centre for the Health Services; and Health Systems Research Unit, Medical Research Council of South Africa
Jack Moodley University of Kwazulu Natal, Durban, South Africa
Olufemi Oladapo WHO, Geneva, Switzerland
Annie Portela WHO, Geneva, Switzerland
Jim Roberts Magee-Women’s Research Institute, Pittsburgh, United States
Jeffrey Michael Smith USAID MCS, Washington DC, United States
Eleni Tsigas Preeclampsia Foundation, Florida United States
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1. Global Pregnancy CoLaboratory (CoLab)
Current Projects
PRINCIPAL INVESTIGATOR PROJECT TITLE
Mandy BellSponsor: Carl Hubel
Variation in endoglin pathway genes associated with pre-eclampsia
Lucy Chappell (Lucilla Poston and Hannele Laivuori)
Understanding, diagnosing and predicting pregnancy outcome in women with chronic hypertension
Sandra FoundsSponsor: James Roberts
Biomarker assay development for translation of discovery-based placental mRNA candidates to serum protein concentrations in early pregnancy to predict pre-eclampsia
Stefan Hansson w/Maya Jalmby
Inflammatory profiling of pre-eclampsia, highlighting fetal gender, parity, BMI and IUGR: a case control study
Roberta Ness Metabolic traits and risk of pre-eclampsia: a mendelian randomisation study
Bimla SchwartzSponsor: James Roberts
Lactation, pre-eclampsia, and maternal risk of CVD
Annetine Staff Maternal circulating angiogenic factors and subtypes of pre-eclampsia
Sarah Schalekamp-Timmermans and Eric Steegers
Sex specific differences in the placental syndrome and markers of placentation
Ellen O’NealSponsor: Thomas McElrath,
Urinary tract infection and risk of pre-eclampsia
2. Memberships
COHORT MEMBER/CENTRE AFFILIATION
Ohio State Patient Cohort Catalin S. BuhimschiColumbus, USA
PRE-EMPT Manager * Sharla DrebitVancouver, Canada
NIH/NICHD Placental Bank Susan J. FisherSan Francisco, USA
GAPPS—Global Alliance to Prevent Prematurity and Stillbirth
Michael G. GravettSeattle, USA
Lund Database Stefan HanssonLund, Sweden
COHORT MEMBER/CENTRE AFFILIATION
POUCH Study Claudia HolzmanEast Lansing, USA
PEPP—Prenatal Exposures and Preeclampsia Prevention
Arun Jeyabalan Pittsburgh, USA
INTERBIO 21st Stephen Kennedy Oxford, UK
RANDERS Ulla Breth KnudsenAarhus, Denmark
FINNPEC and PREDO Hannele LaivuoriHelsinki, Finland
Avon Longitudinal Study of Parents and Children Deborah A. Lawlor Bristol, UK
Life Codes Thomas Frederick McElrath Boston, USA
Canadian Perinatal Network Laura A. Magee Vancouver, Canada
The Norwegian Mother and Child Cohort-MoBa * Per Magnus Oslo, Norway
University of Zimbabwe * Stephen MunjanjaHarare, Zimbabwe
University of Texas at San Antonio Placental Bank
Leslie MyattSan Antonio, USA
SCOPE, BASELINE (Children of SCOPE) and IMPROvED
Jenny MyersManchester, UK
Co-Investigator * Roberta B. NessHouston, USA
Danish Birth Cohort Jorn OlsenAarhus, Denmark
VIP Study Lucilla PostonLondon, UK
Co-InvestigatorOxford Biobank
* Christopher WG RedmanOxford, UK
ICDDR Laura ReichenbachDhaka, Bangladesh
Principal Investigator * James M. RobertsPittsburgh, USA
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COHORT MEMBER/CENTRE AFFILIATION
Pregnancy Outcomes Prediction Study Gordon C S SmithCambridge, UK
CHASE Biobank Anne Cathrine StaffOslo, Norway
Generation R Eric A.P. Steegers Rotterdam, The Netherlands
Mass General Biobank Ravi ThadhaniBoston, USA
Principal Investigator: PRE-EMPT * Peter von Dadelszen Vancouver, Canada
Omega Collection * Michelle A. WilliamsBoston, USA
Tri-HELLP Melissa WilsonLos Angeles, USA
Beijing Cohort Yan-ling WangBeijing, China
Epidemiology Division NIH/NICHD Cuilin Zhang Rockville, USA
3. COLAB Membership Policy
• Apply to the Executive Committee
• Participate by collaborating with other members of COLAB
• One voting member per cohort
Information to be provided:
1. Name, address, telephone, e-mail address, and fax number
2. Area of current pregnancy related research to be extended by participation in COLAB
3. Current departmental position and funding
4. Abbreviated CV, one page
What is the expected contribution to the work of COLAB?
1. Share a limited data set with the secure central COLAB database
2. Allow the use of data and biosamples on a proposal by proposal basis
3. Abide by the policies of the COLAB (publication and protocol approval)
4. Sign memorandum of understanding of COLAB
Criteria for accepting a new member:
1. Research interests relevant to COLAB, namely complication(s) of pregnancy
2. Has excellent data and/or biological samples
3. Aware that active participation is expected
If deemed unsuitable by a majority vote of the Steering Committee, the reason for will be simply and politely stated to the applicant. They may reapply once problems are addressed by applicant and the Steering Committee agrees that re-application is appropriate.
Criteria for continuing membership:
1. To be reviewed by Steering Committee for continuation as a member after 3 years
COLAB Appendix 3:
4. Administrative Structure
I. Executive Committee
A. Responsibilities
1. Organize meetings of the GPC.
2. Resolve conflicts.
3. Assure adherence to regulatory issues of studies and activities of the GPC.
4. Guarantee adherence to deadlines set by the Grantors.
5. Provide leadership to assure the GPC is a sustainable source of studies of adverse pregnancy outcomes. These studies will initially address issues relevant to pre-eclampsia using data and biosamples from current member cohorts and then extend to addressing other relevant outcomes with participation of low and middle-income countries (LMIC).
B. Membership
1. Non-voting Chair (would vote to resolve ties in the absence of a full complement of Executive Committee members).
2. Four elected members from the Steering Committee
3. Voting ex-officio members
a. The Principal and Co-investigators of the supporting grant
b. A member selected by the Executive Committee from a LMIC
C. Elected members of the Executive Committee will be selected and elected by the Steering Committee every three years. The Chair will be elected from the Executive Committee by the Executive Committee for a three-year term.
There will be two exceptions during the first cycle of the Executive Committee:
1. The PI of the CoLaboratory will serve as Chair for the first three years.
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2. Two of the elected members shall serve three years and two shall serve four years (to facilitate continuity)
II. The Steering Committee of the Global Pregnancy CoLaboratory
A. The Steering Committee shall have the following responsibilities:
1. To present their own proposals or those that they sponsor for others. The steering committee member is responsible for the timely conduct and adherence to regulatory requirements of all proposals that the member sponsors.
2. To approve protocols and set time lines for their start and completion
3. To approve and renew membership applications.
B. The Steering Committee shall be made up of one member from each participating cohort.
C. The Steering Committee will meet electronically monthly with at least one annual in-person meeting.
1. The Chair will circulate an Agenda and copies of submitted protocols to Steering Committee members at least one week prior to the monthly meeting. If a Steering Committee member cannot participate in the meeting, that member may appoint a voting delegate to participate in his/her place.
D. Votes by the Steering Committee shall be decided by a majority of the Steering Committee or two-thirds of the members and delegates present at a meeting.
5. Publications Policy
I. Authorship
A. The first author of the primary paper resulting from a project will be determined by the project PI.
B. Other authors include other individuals involved in the performance of the project, members of the Project Committee, and representatives of the centres that contributed data and/or samples.
1. Members of the Executive Committee may apply for membership on Project committees to achieve authorship (this is especially relevant to the PI and CoI’s who do not have cohorts yet are actively involved in activities).
2. Authorship responsibilities require reading and critiquing the paper.
C. Although there will usually be one author per cohort, if justification exists more than one may be included. Justification includes but is not limited to: multiple contributing subcohorts, or where participation requires substantial input from several individuals.
D. The order of authors is determined by the Project Committee with justification and is approved by the Steering Committee who will also determine if authorship requirements for publication have been met: Uniform Requirements for Manuscripts Submitted to Biomedical Journals (ICMJE) http://www.icmje.org/.
II. Acknowledgements
A. All publications will acknowledge the Global Pregnancy CoLaboratory of PRE-EMPT.
B. Publications will acknowledge “Centers” collaborating or providing samples or data to a participating cohort.
PRE-EMPT Co-ordinating CentreThe University of British ColumbiaDepartment of Obstetrics and GynaecologyV3-341, 950 West 28th AvenueVancouver, British ColumbiaCanada V5Z 4H4
+1 (604) 875-2424 ext [email protected]://pre-empt.cfri.ca
Chief Editor: Peter von DadelszenEditors: Sumedha Sharma, Sharla DrebitGraphic Design: Grove Media
[We have converted] the concept of the PIERS on the Move app into a reality that has now guided the antenatal care of women in Nigeria, Pakistan and India for over 14,000 visits, and resulting in over 250 urgent and non-urgent referrals to facility.
—Peter von Dadelszen